Multiheteroaryl compounds as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases

ABSTRACT

Multiheteroaryl compounds, their preparation, pharmaceutical compositions comprising these compounds, and their pharmaceutical use in the prevention and treatment of prostaglandin D 2  mediated diseases and conditions that may be modulated by the inhibition of hematopoietic prostaglandin D synthase (H-PGDS).

CROSS REFERENCE TO RELATED APPLICATIONS

The present invention claims priority from U.S. Provisional ApplicationNo. 61/098,942 filed Sep. 22, 2008 entitled “Multiheterocyclic Compoundsfor the Treatment of Allergy, Inflammation, and Immune Disorders.”

FIELD OF THE INVENTION

Multiheteroaryl compounds, their preparation, pharmaceuticalcompositions comprising these compounds, and their pharmaceutical use inthe prevention and treatment of prostaglandin D₂ mediated diseases andconditions that may be modulated by the inhibition of hematopoieticprostaglandin D synthase (H-PGDS).

BACKGROUND OF THE INVENTION

Allergic and inflammatory disorders such as allergic rhinitis, asthma,chronic obstructive pulmonary disease (COPD), allergic conjunctivitis,and atopic dermatitis affect roughly one-fifth of the world population.Symptoms arising from antigenic challenge, includingbronchoconstriction, bronchial hyperactivity, sneezing, nasal discharge,and nasal congestion, have been shown to correspond with the release ofmultiple mediators from inflammatory cells. Current therapies thateffectively treat some of these symptoms have arisen out of compoundclasses including antihistamines, leukotriene antagonists, andcorticosteroids. Many existing medicines suffer from side effects suchas headache, sleepiness, sedation, dyspepsia, hydrodipsia, pharyngitis,and oral candidiasis. In addition, many of these individual therapies,although treating some symptoms, may fail to address a broader range ofsymptoms that affect patient quality of life. Antihistamines, forexample, treat some of the most unpleasant symptoms of allergy, but havelittle therapeutic benefit against nasal congestion.

Immunological challenge results in the release of prostaglandin D₂(PGD₂), the primary allergic and inflammatory mediator, frominflammatory cells. PGD₂, a metabolite of arachidonic acid, activatesboth the DP₁ (DP) and DP₂ (CRTH2) receptors, which play a central rolein airway inflammation (Spik, I., Brenuchon, C., Angeli, V., et al. J.Immunol., 174, 2005, 3703-3708; Urade, Y., Hayaishi, O. Vitamin andHormones, 58, 2000, 89-120).

Prostaglandin D synthase (PGDS) catalyzes the conversion of the commonprostanoid precursor prostaglandin H₂ (PGH₂) to PGD₂. Two distinct formsof PGDS, lipocalin PGDS (L-PGDS) and hematopoietic PGDS (H-PGDS) havebeen identified and characterized (Kapoor, M., Kojima, F., Yang, L., andCrofford, L. J. Prostaglandins Leukot. Essent. Fatty Acids, 76(2), 2007,103-112; Herlong, J. L., Scott, T. R. Immunology Letters, 102, 2006,121-131; Urade, Y., Fujimoto, N., and Hayaishi, O. J. Biol. Chem., 260,1985, 12410-12415; Kanaoka, Y., Ago, H., Inagaki, E., et al. Cell, 90,1997, 1085-1095).

L-PGDS is a glutathione-independent 26 kDa secretory protein that isregarded as the major generator of PGD₂ in the central nervous system.L-PGDS is involved in the regulation of sleep (Pinzar, E., Kanaoka, Y.,Inui, T., Eguchi, N., Urade, Y., and Hayaishi, O. Proc. Natl. Acad. Sci.U.S.A., 97, 2000, 4903-4907) and pain (Eguchi, N., Minami, T.,Shirafuji, N., et al. Proc. Natl. Acad. Sci. U.S.A., 96, 1999, 726-730).

H-PGDS is a 26 kDa cytosolic protein that catalyzes the conversion ofPGH₂ to PGD₂ in a glutathione-dependent manner. This sigma classglutathione S-transferase (GST) is localized in mast cells,antigen-presenting cells, and Th2 cells, and is involved in allergic andinflammatory response (Urade, Y., Mohri, I., Aritake, K., Inoue, T.,Miyano, M. Functional and Structural Biology on the Lipo-network, 2006,135-164; Kanaoka, Y., Urade, Y. Prostaglandins Leukot. Essent. FattyAcids, 69, 2003, 163-167).

H-PGDS inhibition provides a novel method for preventing and/or treatingallergic and respiratory diseases or conditions through the suppressionof PGD₂ synthesis. Most current therapies function subsequent to mastcell activation and/or degranulation and the formation and release ofPGD₂. H-PGDS inhibitors, however, have been found to block the formationof PGD₂ in vitro (Ikai, K., Ujihara, M., Fujii, K., Urade, Y.Biochemical Pharmacology, 38(16), 1989, 2673-2676). In addition, theweak H-PGDS inhibitor HQL-79 has shown antiallergic and antiasthmaticactivity in vivo (Matsushita, N., Hizue, M., Aritake, K., et al. Jpn. J.Pharmacol., 78, 1998, 1-10; Matsushita, N., Aritake, K., Takada, A., etal. Jpn. J. Pharmacol., 78, 1998, 11-22). Other PGDS inhibitors havebeen reported (US Patent Application No. US 2008/0146569 A1; PCTInternational Application No. WO 2007/041634 A1; PCT InternationalApplication No. WO 2005/094805 A1; PCT International Application No. WO2007/007778).

Evidence suggests that the modulation of H-PGDS activity should be oftherapeutic benefit in indications related to elevated PGD₂ levels.These indications include, but are not limited to, allergic rhinitis,perennial rhinitis, rhinorrhea, nasal congestion, nasal inflammation,all types of asthma, COPD, allergic conjunctivitis, arthritis, atopicdermatitis and other types of dermal inflammation, ocular inflammation,wound healing, dermal scarring, and muscular necrosis (i.e. Duchennemuscular dystrophy; American Journal of Pathology, 174(5), 2009,1735-1744). Efficacious doses of H-PGDS inhibitors may provide boththerapeutic benefits and improved safety profiles over existingtherapies used for these indications. Recent evidence also suggests thatPGD₂ produced by H-PGDS plays a role in fever induction (Journal ofPhysiology and Pharmacology, 60(2), 2009, 145-150).

Compounds have now been found that are inhibitors of H-PGDS, and atexpected efficacious doses, do not significantly inhibit L-PGDS.

SUMMARY OF THE INVENTION

The exemplary embodiments may be directed to multiheterocyclic(multiheteroaryl) compounds of structural formulas (I) or (II),respectively, that may be used to treat or prevent allergic,inflammatory, and/or immune disorders, including the prevention andtreatment of prostaglandin D₂ mediated diseases and conditions that maybe modulated by the inhibition of hematopoietic prostaglandin D synthase(H-PGDS), wherein R¹, R², U¹, U², U³, U⁴, Y¹, Y², Y³, Y⁴, and W, aredefined herein:

Another aspect of the exemplary embodiments may be a pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundaccording to either of formulas (I) or (II), or an equivalent thereof,or an N-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof, in admixture with a pharmaceutically acceptable carrier.

Another aspect of the exemplary embodiments may be directed to a methodof treating immunological disorders, particularly allergic and/orinflammatory disorders, and more particularly disorders such as allergicrhinitis, asthma, chronic obstructive pulmonary disease (COPD),arthritis, dermal inflammation, ocular inflammation, wound healing, anddermal scarring in a patient in need thereof by administering to thepatient a compound according to either formula (I) or (II), or ahydrate, solvate, or N-oxide thereof, or a pharmaceutically acceptablesalt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The exemplary embodiments may be directed bicyclic heteroaryl compoundsof formulas (I) or (II), respectively, their preparation, pharmaceuticalcompositions comprising these compounds, and their pharmaceutical use inthe prevention and treatment of prostaglandin D₂ mediated diseases andconditions that may be modulated by the inhibition of hematopoieticprostaglandin D synthase (H-PGDS).

The compound of formula (I), according to one exemplary embodiment, isshown below:

wherein:

R¹ is (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, phenyl, 2-pyridyl, 3-pyridyl,or 4-pyridyl; wherein each phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl ofR¹ may be optionally substituted with no more than two of each or acombination of fluoro, hydroxy, —CH₂OH, carboxy, carboxymethyl, orcarboxyethyl;

R² is —(CH₂)_(n)Z¹ or —(CH₂)_(n)Z²;

n is 0, 1, 2, 3, or 4;

Z¹ is hydrogen, OR³, C(O)R³, CO₂R³, C(O)NR⁴R⁵, SO₂NR⁴R⁵, SO₂R³,(C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, (C₃-C₆)-alkenyl, (C₃-C₆)-alkynyl,(C₆-C₁₄)-aryl, (CH₂)_(p)CF₃, a five- to ten-membered heteroaryl,

or a three- to ten-membered heterocycle; wherein any one nitrogen atomof any heterocycle containing one or more nitrogen atoms that may besubstituted with a non-ring atom are substituted with —(CH₂)_(q)Q;

Z² is cyano, trifluoromethyl, (CF₂)_(p)CF₃, SR³, NR⁴R⁵, N(H)C(O)R³,N(H)CO₂R³, N(H)C(O)NR⁴R⁵, N(H)SO₂R³, vinyl, or ethynyl when n is 1, 2, 3or 4;

Z² may also be cyano, trifluoromethyl, (CF₂)_(p)CF₃, SR³, NR⁴R⁵,N(H)C(O)R³, N(H)CO₂R³, N(H)C(O)NR⁴R⁵, N(H)SO₂R³, vinyl, or ethynyl whenn is 0, except when R² is covalently bonded to a U¹, U², U³, or U⁴ thatis a nitrogen atom;

R³ is hydrogen, (C₁-C₆)-alkyl, trifluoromethyl, (C₃-C₆)-alkenyl,(C₃-C₆)-alkynyl, (CH₂)_(m)(C₃-C₆)-cycloalkyl, (CH₂)_(m)phenyl,(CH₂)_(m)-(five- to ten-membered heteroaryl), or (CH₂)_(m)(three- toten-membered heterocycle), wherein any one nitrogen atom of anyheterocycle containing one or more nitrogen atoms that may besubstituted with a non-ring atom are substituted with —(CH₂)_(q)Q;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q is hydrogen, (C₁-C₆)-alkyl, (CH₂)_(p)CF₃, (C₃-C₆)-alkenyl,(C₃-C₆)-alkynyl, (C₃-C₆)-cycloalkyl, (C₆-C₁₄)-aryl, C(O)R³, CO₂R³,C(O)NR⁴R⁵, a three- to six-membered heterocycle, or a five- toten-membered heteroaryl when q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO₂NR⁴R⁵ when q is 1, 2, 3, or4;

Q may also be hydroxy, (C₁-C₆)-alkoxy, sulfhydryl, —S—(C₁-C₆)-alkyl, orNR⁴R⁵ when q is 2, 3, or 4;

p is 1, 2, or 3;

R³ may also be vinyl or ethynyl when R³ is not covalently bonded to an Nor O atom;

R³ may also be vinyl or ethynyl when R³ is not covalently bonded to an Satom possessing a −2 (minus 2) oxidation state;

R⁴ and R⁵ are independently hydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-alkenyl,(C₃-C₆)-alkynyl, (CH₂)_(m)(C₃-C₆)-cycloalkyl, (CH₂)_(m)phenyl,(CH₂)_(m)-(three- to ten-membered heterocycyl), or (CH₂)_(m)-(five- toten-membered heteroaryl);

the NR⁴R⁵ group of any C(O)NR⁴R⁵, SO₂NR⁴R⁵, NR⁴R⁵, or N(H)C(O)NR⁴R⁵ mayalso form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine,or a thiomorpholine S-dioxide;

the NR⁴R⁵ group of any C(O)NR⁴R⁵, SO₂NR⁴R⁵, NR⁴R⁵, or N(H)C(O)NR⁴R⁵ mayalso form a piperazine ring, wherein the other nitrogen atom of thepiperazine ring is substituted with hydrogen, (C₁-C₆)-alkyl, CH₂CF₃,(C₃-C₆)-cycloalkyl, CH₂(C₃-C₆)-cycloalkyl, phenyl, benzyl, hydroxyethyl,or hydroxypropyl;

phenyl or heteroaryl rings of Z¹ and Z² are optionally substituted withone-to-three of any one or combination of the following: halo, hydroxy,sulfhydryl, (C₁-C₃)-alkoxy, (C₁-C₃)-alkyl, (C₁-C₃)-alkylthio,trifluoromethyl, trifluoromethoxy, cyano, carboxy, carboxy(C₁-C₃)-alkyl,carbamoyl, or sulfamoyl;

W is a covalent bond, O, S, SO, SO₂, CH₂, CHOH, CO, or NH;

U¹, U², U³, U⁴, and a carbon atom form a five-membered heteroaryl ring;wherein one of U¹, U², U³, and U⁴ of the five-membered heteroaryl ringis covalently bonded to the R² group; wherein the U¹, U², U³, or U⁴ thatis covalently bonded to the R² group is a carbon atom or a nitrogenatom; wherein when the U¹, U², U³, or U⁴ that is covalently bonded tothe R² group is a nitrogen atom, one, two, or all of the other three ofthe group consisting of U¹, U², U³, and U⁴ is N and each remaining ofthe group consisting of U¹, U², U³, and U⁴ that is not N is C—R⁶;wherein when the U¹, U², U³, or U⁴ that is covalently bonded to the R²group is a carbon atom, one of the other three of the group consistingof U¹, U², U³, and U⁴ is N—R⁶, O, or S, and each of remaining of thegroup consisting of U¹, U², U³, and U⁴ is C—R⁶ or N;

Y¹, Y², Y³, a nitrogen atom, and two carbon atoms form a six-memberedheteroaryl ring; wherein no more than one of the group consisting of Y¹,Y², and Y³ is N; and wherein all Y¹, Y², and Y³ that are not N are C—R⁶;

each R⁶ is independently hydrogen, methyl, trifluoromethyl, or amino;and

-   -   each R⁷ is independently hydrogen or methyl;        or an equivalent thereof, or an N-oxide thereof, or a        pharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(II):

wherein:

R¹ is (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, phenyl, 2-pyridyl, 3-pyridyl,or 4-pyridyl; wherein each phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl ofR¹ may be optionally substituted with no more than two of each or acombination of fluoro, hydroxy, —CH₂OH, carboxy, carboxymethyl, orcarboxyethyl;

R² is —(CH₂)_(n)Z¹ or —(CH₂)_(n)Z²;

n is 0, 1, 2, 3, or 4;

Z¹ is hydrogen, OR³, C(O)R³, CO₂R³, C(O)NR⁴R⁵, SO₂NR⁴R⁵, SO₂R³,(C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, (C₃-C₆)-alkenyl, (C₃-C₆)-alkynyl,(C₆-C₁₄)-aryl, (CH₂)_(p)CF₃, a five- to ten-membered heteroaryl,

or a three- to ten-membered heterocycle; wherein any one nitrogen atomof any heterocycle containing one or more nitrogen atoms that may besubstituted with a non-ring atom are substituted with —(CH₂)_(q)Q;

Z² is cyano, trifluoromethyl, (CF₂)_(p)CF₃, SR³, NR⁴R⁵, N(H)C(O)R³,N(H)CO₂R³, N(H)C(O)NR⁴R⁵, N(H)SO₂R³, vinyl, or ethynyl when n is 1, 2, 3or 4;

Z² may also be cyano, trifluoromethyl, (CF₂)_(p)CF₃, SR³, NR⁴R⁵,N(H)C(O)R³, N(H)CO₂R³, N(H)C(O)NR⁴R⁵, N(H)SO₂R³, vinyl, or ethynyl whenn is 0, except when R² is covalently bonded to a U¹, U², U³, or U⁴ thatis a nitrogen atom;

R³ is hydrogen, (C₁-C₆)-alkyl, trifluoromethyl, (C₃-C₆)-alkenyl,(C₃-C₆)-alkynyl, (CH₂)_(m)(C₃-C₆)-cycloalkyl, (CH₂)_(m)phenyl,(CH₂)_(m)-(five- to ten-membered heteroaryl), or (CH₂)_(m)(three- toten-membered heterocycle); wherein any one nitrogen atom of anyheterocycle containing one or more nitrogen atoms that may besubstituted with a non-ring atom are substituted with —(CH₂)_(q)Q;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q is hydrogen, (C₁-C₆)-alkyl, (CH₂)_(p)CF₃, (C₃-C₆)-alkenyl,(C₃-C₆)-alkynyl, (C₃-C₆)-cycloalkyl, (C₆-C₁₄)-aryl, C(O)R³, CO₂R³,C(O)NR⁴R⁵, a three- to six-membered heterocycle, or a five- toten-membered heteroaryl when q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO₂NR⁴R⁵ when q is 1, 2, 3, or4;

Q may also be hydroxy, (C₁-C₆)-alkoxy, sulfhydryl, —S—(C₁-C₆)-alkyl, orNR⁴R⁵ when q is 2, 3, or 4;

p is 1, 2, or 3;

R³ may also be vinyl or ethynyl when R³ is not covalently bonded to an Nor O atom;

R³ may also be vinyl or ethynyl when R³ is not covalently bonded to an Satom possessing a −2 (minus 2) oxidation state;

R⁴ and R⁵ are independently hydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-alkenyl,(C₃-C₆)-alkynyl, (CH₂)_(m)(C₃-C₆)-cycloalkyl, (CH₂)_(m)phenyl,(CH₂)_(m)-(three- to ten-membered heterocycyl), or (CH₂)_(m)-(five- toten-membered heteroaryl);

the NR⁴R⁵ group of any C(O)NR⁴R⁵, SO₂NR⁴R⁵, NR⁴R⁵, or N(H)C(O)NR⁴R⁵ mayalso form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine,or a thiomorpholine S-dioxide;

the NR⁴R⁵ group of any C(O)NR⁴R⁵, SO₂NR⁴R⁵, NR⁴R⁵, or N(H)C(O)NR⁴R⁵ mayalso form a piperazine ring, wherein the other nitrogen atom of thepiperazine ring is substituted with hydrogen, (C₁-C₆)-alkyl, CH₂CF₃,(C₃-C₆)-cycloalkyl, CH₂(C₃-C₆)-cycloalkyl, phenyl, benzyl, hydroxyethyl,or hydroxypropyl;

phenyl or heteroaryl rings of Z¹ and Z² are optionally substituted withone-to-three of any one or combination of the following: halo, hydroxy,sulfhydryl, (C₁-C₃)-alkoxy, (C₁-C₃)-alkyl, (C₁-C₃)-alkylthio,trifluoromethyl, trifluoromethoxy, cyano, carboxy, carboxy(C₁-C₃)-alkyl,carbamoyl, or sulfamoyl;

W is a covalent bond, O, S, SO, SO₂, CH₂, CHOH, CO, or NH;

U¹, U², U³, U⁴, and a carbon atom form a five-membered heteroaryl ring;wherein one of U¹, U², U³, and U⁴ of the five-membered heteroaryl ringis covalently bonded to the R² group; wherein the U¹, U², U³, or U⁴ thatis covalently bonded to the R² group is a carbon atom or a nitrogenatom; wherein when the U¹, U², U³, or U⁴ that is covalently bonded tothe R² group is a nitrogen atom, one, two, or all of the other three ofthe group consisting of U¹, U², U³, and U⁴ is N and each remaining ofthe group consisting of U¹, U², U³, and U⁴ that is not N is C—R⁶;wherein when the U¹, U², U³, or U⁴ that is covalently bonded to the R²group is a carbon atom, one of the other three of the group consistingof U¹, U², U³, and U⁴ is N—R⁶, O, or S, and each of remaining of thegroup consisting of U¹, U², U³, and U⁴ is C—R⁶ or N;

Y⁴ is O, S, or N—R⁷;

each R⁶ is independently hydrogen, methyl, trifluoromethyl, or amino;and

each R⁷ is independently hydrogen or methyl;

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

A more specific subset of exemplary embodiments derived from formula (I)are shown below individually as formulas (III)-(XIX), respectively.

One such exemplary embodiment may be directed to a compound of formula(III)

wherein:

each X¹, X², X³, X⁴, and X⁵ is independently hydrogen or fluoro, with nomore than two of X¹, X², X³, X⁴, and X⁵ being fluoro;

Y³ is CH or N;

each R⁶ is independently hydrogen, methyl, trifluoromethyl, or amino;

n is 0, 1, 2, 3, or 4;

Z¹ is hydrogen, OR³, C(O)R³, CO₂R³, C(O)NR⁴R⁵, SO₂NR⁴R⁵, SO₂R³,(C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, (C₃-C₆)-alkenyl, (C₃-C₆)-alkynyl,(C₆-C₁₄)-aryl, (CH₂)_(p)CF₃, a five- to ten-membered heteroaryl,

or a three- to ten-membered heterocycle; wherein any one nitrogen atomof any heterocycle containing one or more nitrogen atoms that may besubstituted with a non-ring atom are substituted with —(CH₂)_(q)Q;

R³ is hydrogen, (C₁-C₆)-alkyl, trifluoromethyl, (C₃-C₆)-alkenyl,(C₃-C₆)-alkynyl, (CH₂)_(m)(C₃-C₆)-cycloalkyl, (CH₂)_(m)phenyl,(CH₂)_(m)-(five- to ten-membered heteroaryl), or (CH₂)_(m)-(three- toten-membered heterocycle); wherein any one nitrogen atom of anyheterocycle containing one or more nitrogen atoms that may besubstituted with a non-ring atom are substituted with —(CH₂)_(q)Q;

R⁴ and R⁵ are independently hydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-alkenyl,(C₃-C₆)-alkynyl, (CH₂)_(m)(C₃-C₆)-cycloalkyl, (CH₂)_(m)phenyl,(CH₂)_(m)-(three- to ten-membered heterocycyl), (CH₂)_(m)-(five- toten-membered heteroaryl);

the NR⁴R⁵ group of any C(O)NR⁴R⁵, SO₂NR⁴R⁵, NR⁴R⁵, or N(H)C(O)NR⁴R⁵ mayalso form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine,or a thiomorpholine S-dioxide;

the NR⁴R⁵ group of any C(O)NR⁴R⁵, SO₂NR⁴R⁵, NR⁴R⁵, or N(H)C(O)NR⁴R⁵ mayalso form a piperazine ring, wherein the other nitrogen atom of thepiperazine ring is substituted with hydrogen, (C₁-C₆)-alkyl, CH₂CF₃,(C₃-C₆)-cycloalkyl, CH₂(C₃-C₆)-cycloalkyl, phenyl, benzyl, hydroxyethyl,or hydroxypropyl;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q is hydrogen, (C₁-C₆)-alkyl, (CH₂)_(p)CF₃, (C₃-C₆)-alkenyl,(C₃-C₆)-alkynyl, (C₃-C₆)-cycloalkyl, (C₆-C₁₄)-aryl, C(O)R³, CO₂R³,C(O)NR⁴R⁵, a three- to six-membered heterocycle, or a five- toten-membered heteroaryl;

Q may also be cyano, trifluoromethyl, or SO₂NR⁴R⁵ when q is 1, 2, 3, or4;

Q may also be hydroxy, (C₁-C₆)-alkoxy, sulfhydryl, —S—(C₁-C₆)-alkyl, orNR⁴R⁵ when q is 2, 3, or 4;

p is 1, 2, or 3;

phenyl or heteroaryl rings of Z¹ are optionally substituted withone-to-three of any one or combination of the following: halo, hydroxy,sulfhydryl, (C₁-C₃)-alkoxy, (C₁-C₃)-alkyl, (C₁-C₃)-alkylthio,trifluoromethyl, trifluoromethoxy, cyano, carboxy, carboxy(C₁-C₃)-alkyl,carbamoyl, or sulfamoyl; and

R⁷ is hydrogen or methyl;

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(IV):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein n, Z¹, R⁶, Y³, X¹, X², X³,X⁴, and X⁵ are as defined above for a compound of Formula (III).

Another exemplary embodiment may be directed to a compound of formula(V):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein n, Z¹, R⁶, Y³, X¹, X², X³,X⁴, and X⁵ are as defined above for a compound of Formula (IV).

Another exemplary embodiment may be directed to a compound of formula(VI):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein each X¹, X², X³, X⁴, and X⁵is independently hydrogen or fluoro, with no more than two of X¹, X²,X³, X⁴, and X⁵ being fluoro; and wherein n, Z¹, R⁶, and Y³ are asdefined above for a compound of Formula (I).

Another exemplary embodiment may be directed to a compound of formula(VII):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein n, Z¹, R⁶, Y³, X¹, X², X³,X⁴, and X⁵ are as defined above for a compound of Formula (VI).

Another exemplary embodiment may be directed to a compound of formula(VIII):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein n, Z¹, R⁶, Y³, X¹, X², X³,X⁴, and X⁵ are as defined above for a compound of Formula (VI).

Another exemplary embodiment may be directed to a compound of formula(IX):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein each X¹, X², X³, X⁴, and X⁵is independently hydrogen or fluoro, with no more than two of X¹, X²,X³, X⁴, and X⁵ being fluoro; and wherein n, Z¹, R⁶, and Y³ are asdefined above for a compound of Formula (I).

Another exemplary embodiment may be directed to a compound of formula(X):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein n, Z¹, R⁶, Y³, X¹, X², X³,X⁴, and X⁵ are as defined above for a compound of Formula (IX).

Another exemplary embodiment may be directed to a compound of formula(XI):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein n, Z¹, R⁶, Y³, X¹, X², X³,X⁴, and X⁵ are as defined above for a compound of Formula (IX).

Another exemplary embodiment may be directed to a compound of formula(XII):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein W is a covalent bond, oxygenatom (O), or carbonyl group (CO), and wherein each X¹, X², X³, X⁴, andX⁵ is independently hydrogen or fluoro, with no more than two of X¹, X²,X³, X⁴, and X⁵ being fluoro; and wherein n, Z¹, R⁶, and Y³ are asdefined above for a compound of Formula (I).

Another exemplary embodiment may be directed to a compound of formula(XIII):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein n, Z¹, R⁶, Y³, W, X¹, X²,X³, X⁴, and X⁵ are as defined above for a compound of Formula (XII).

Another exemplary embodiment may be directed to a compound of formula(XIV):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein n, Z¹, R⁶, Y³, W, X¹, X²,X³, X⁴, and X⁵ are as defined above for a compound of Formula (XII).

Another exemplary embodiment may be directed to a compound of formula(XV):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein W is a covalent bond, oxygenatom (O), or carbonyl group (CO); and wherein each X¹, X², X³, X⁴, andX⁵ is independently hydrogen or fluoro, with no more than two of X¹, X²,X³, X⁴, and X⁵ being fluoro; and wherein n, Z¹, R⁶, and Y³ are asdefined above for a compound of Formula (I).

Another exemplary embodiment may be directed to a compound of formula(XVI):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein n, Z¹, R⁶, Y³, W, X¹, X²,X³, X⁴, and X⁵ are as defined above for a compound of Formula (XV).

Another exemplary embodiment may be directed to a compound of formula(XVII):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein n, Z¹, R⁶, Y³, W, X¹, X²,X³, X⁴, and X⁵ are as defined above for a compound of Formula (XV).

Another exemplary embodiment may be directed to a compound of formula(XVIII):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein W is a covalent bond, oxygenatom (O), or carbonyl group (CO); and wherein each X¹, X², X³, X⁴, andX⁵ is independently hydrogen or fluoro, with no more than two of X¹, X²,X³, X⁴, and X⁵ being fluoro; and wherein n, Z¹, and Y³ are as definedabove for a compound of Formula (I).

Another exemplary embodiment may be directed to a compound of formula(XIX):

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, wherein n, Z¹, Y³, W, X¹, X², X²,X³, X⁴, and X⁵ are as defined above for a compound of Formula (XVIII).

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R¹ is phenyl or 3-fluorophenyl; or an equivalentthereof, or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R¹ is phenyl; or an equivalent thereof, or anN-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R¹ is 3-fluorophenyl; or an equivalent thereof, oran N-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 2-pyridyl, 3-pyridyl, or 4-pyridyl; or anequivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II) wherein R² is phenyl; or an equivalent thereof, or anN-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II) wherein R² is 3-fluorophenyl; or an equivalent thereof, oran N-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be directed to a compound of formula(I) wherein R² is benzyl; or an equivalent thereof, or an N-oxidethereof, or a pharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II) wherein R² is 2-pyridylmethyl, 3-pyridylmethyl, or4-pyridylmethyl; or an equivalent thereof, or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is attached to a carbon atom of the adjacentaromatic ring and is

or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is attached to a carbon atom of the adjacentaromatic ring and is

all of E-geometry; or an equivalent thereof, or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is attached to a carbon atom of the adjacentaromatic ring and is

all of E-geometry, or an equivalent thereof, or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is attached to a carbon atom of the adjacentaromatic ring and is

all of E-geometry; or an equivalent thereof, or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted with—(CH₂)_(q)Q; wherein q is 0, 1, 2, 3, or 4; wherein Q is hydrogen,(C₁-C₆)-alkyl, CH₂CF₃, (C₃-C₆)-alkenyl, (C₃-C₆)-alkynyl,(C₃-C₆)-cycloalkyl, (C₆-C₁₄)-aryl, C(O)R³, CO₂R³, C(O)NR⁴R⁵, a three- tosix-membered heterocycle, or a five- to ten-membered heteroaryl; whereinR³ is hydrogen, (C₁-C₆)-alkyl, trifluoromethyl, (C₃-C₆)-alkenyl,(C₃-C₆)-alkynyl, (CH₂)_(m)(C₃-C₆)-cycloalkyl, (CH₂)_(m)phenyl, or(CH₂)_(m)-(five- to ten-membered heteroaryl); wherein m is 0, 1, 2, 3,or 4; wherein R³ may further be vinyl or ethyl when not covalentlybonded to an N or O atom, or an S atom possessing a −2 (minus two)oxidation state; wherein each R⁴ and R⁵ is independently hydrogen,(C₁-C₆)-alkyl, (C₃-C₆)-alkenyl, (C₃-C₆)-alkynyl,(CH₂)_(m)(C₃-C₆)-cycloalkyl, (CH₂)_(m)phenyl, (CH₂)_(m)-(three- toten-membered heterocycyl), or (CH₂)_(m)-(five- to ten-memberedheteroaryl); wherein the NR⁴R⁵ group of any C(O)NR⁴R⁵, SO₂NR⁴R⁵, NR⁴R⁵,or N(H)C(O)NR⁴R⁵ may also form a pyrrolidine, a piperidine, amorpholine, a thiomorpholine, or a thiomorpholine S-dioxide; wherein theNR⁴R⁵ group of any C(O)NR⁴R⁵, SO₂NR⁴R⁵, NR⁴R⁵, or N(H)C(O)NR⁴R⁵ may alsoform a piperazine ring, wherein the other nitrogen atom of thepiperazine ring is substituted with hydrogen, (C₁-C₆)-alkyl, CH₂CF₃,(C₃-C₆)-cycloalkyl, CH₂(C₃-C₆)-cycloalkyl, phenyl, benzyl, hydroxyethyl,or hydroxypropyl; or an equivalent thereof, or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted with —CH₂Q;wherein Q is phenyl or naphthyl; wherein the phenyl or naphthyl isoptionally substituted with one-to-three of any one or combination ofthe following: halo, hydroxy, sulfhydryl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl,(C₁-C₆)-alkylthio, trifluoromethyl, trifluoromethoxy, cyano, carboxy,carboxy(C₁-C₃)-alkyl, carbamoyl, or sulfamoyl; or an equivalent thereof,or an N-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted withbenzyl; wherein the phenyl ring of the benzyl group is optionallysubstituted with one-to-three of any one or combination of thefollowing: halo, hydroxy, sulfhydryl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl,(C₁-C₆)-alkylthio, trifluoromethyl, trifluoromethoxy, cyano, carboxy,carboxy(C₁-C₃)-alkyl, carbamoyl, or sulfamoyl; or an equivalent thereof,or an N-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted withbenzyl; wherein the phenyl ring of the benzyl group is optionallysubstituted with one or two of any halo, hydroxy, methoxy, methyl,trifluoromethyl, trifluoromethoxy, or cyano; or an equivalent thereof,or an N-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl; wherein the nitrogen atom ofthe piperidinyl ring is substituted with benzyl; or an equivalentthereof, or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted with—(CH₂)_(q)Q; wherein q is 0 or 1; wherein Q is a five- to ten-memberedheteroaryl ring; or an equivalent thereof, or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted with—(CH₂)_(q)Q; wherein q is 0 or 1; wherein Q is 2-pyridyl, 3-pyridyl, or4-pyridyl; or an equivalent thereof, or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted with—(CH₂)_(q)Q; wherein q is 0 or 1; wherein Q is 3-pyridazyl or1-methyl-1H-tetrazol-5-yl; or an equivalent thereof, or an N-oxidethereof, or a pharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted with—CH₂CF₃; or an equivalent thereof, or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl; wherein the nitrogen atom ofthe piperidinyl ring is substituted with —CH₂CF₃; or an equivalentthereof, or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted with(C₁-C₆)-alkyl; or an equivalent thereof, or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted with—(CH₂)_(q)Q; wherein q is 0, 1, or 2; wherein Q is (C₃-C₆)-cycloalkyl;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted withC(O)NHR⁵; wherein R⁵ is (C₁-C₆)-alkyl or (C₃-C₆)-cycloalkyl; or anequivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted withC(O)NHR⁵; wherein R⁵ is methyl; or an equivalent thereof, or an N-oxidethereof, or a pharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted with CO₂R³;wherein R³ is (C₁-C₆)-alkyl or (C₃-C₆)-cycloalkyl; or an equivalentthereof, or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted withC(O)R³; wherein R³ is (C₁-C₆)-alkyl, (CH₂)_(m)(C₃-C₆)-cycloalkyl,(CH₂)_(m)phenyl, (CH₂)_(m)(five- to ten-membered heteroaryl),(CH₂)_(m)(three- to ten-membered heterocycyl); or an equivalent thereof,or an N-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted with—(CH₂)_(q)Q; wherein q is 1, 2, 3, or 4; wherein Q is cyano,trifluoromethyl, or SO₂NR⁴R⁵; wherein each R⁴ and R⁵ is independentlyhydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-alkenyl, (C₃-C₆)-alkynyl,(CH₂)_(m)(C₃-C₆)-cycloalkyl, (CH₂)_(m)phenyl, (CH₂)_(m)-(three- toten-membered heterocycyl), or (CH₂)_(m)-(five- to ten-memberedheteroaryl); wherein m is 0, 1, 2, 3, or 4; wherein the NR⁴R⁵ group ofany C(O)NR⁴R⁵, SO₂NR⁴R⁵, NR⁴R⁵, or N(H)C(O)NR⁴R⁵ may also form apyrrolidine, a piperidine, a morpholine, a thiomorpholine, or athiomorpholine S-dioxide; wherein the NR⁴R⁵ group of any C(O)NR⁴R⁵,SO₂NR⁴R⁵, NR⁴R⁵, or N(H)C(O)NR⁴R⁵ may also form a piperazine ring,wherein the other nitrogen atom of the piperazine ring is substitutedwith hydrogen, (C₁-C₆)-alkyl, CH₂CF₃, (C₃-C₆)-cycloalkyl,CH₂(C₃-C₆)-cycloalkyl, phenyl, benzyl, hydroxyethyl, or hydroxypropyl;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II), wherein R² is 4-piperidinyl, 3-piperidinyl,(3R)-piperidinyl, (3S)-piperidinyl, 3-pyrrolidinyl, (3R)-pyrrolidinyl,(3S)-pyrrolidinyl, or 3-azetidinyl; wherein the nitrogen atom of thepiperidinyl, pyrrolidinyl, or azetidinyl ring is substituted with—(CH₂)_(q)Q; wherein q is 2, 3, or 4; wherein 0 is hydroxy, sulfhydryl,or NR⁴R⁵; wherein each R⁴ and R⁵ is independently hydrogen,(C₁-C₆)-alkyl, (C₃-C₆)-alkenyl, (C₃-C₆)-alkynyl,(CH₂)_(m)(C₃-C₆)-cycloalkyl, (CH₂)_(m)phenyl, (CH₂)_(m)-(three- toten-membered heterocycyl), or (CH₂)_(m)-(five- to ten-memberedheteroaryl); wherein m is 0, 1, 2, 3, or 4; wherein the NR⁴R⁵ group ofany C(O)NR⁴R⁵, SO₂NR⁴R⁵, NR⁴R⁵, or N(H)C(O)NR⁴R⁵ may also form apyrrolidine, a piperidine, a morpholine, a thiomorpholine, or athiomorpholine S-dioxide; wherein the NR⁴R⁵ group of any C(O)NR⁴R⁵,SO₂NR⁴R⁵, NR⁴R⁵, or N(H)C(O)NR⁴R⁵ may also form a piperazine ring,wherein the other nitrogen atom of the piperazine ring is substitutedwith hydrogen, (C₁-C₆)-alkyl, CH₂CF₃, (C₃-C₆)-cycloalkyl,CH₂(C₃-C₆)-cycloalkyl, phenyl, benzyl, hydroxyethyl, or hydroxypropyl;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II) wherein W is a covalent bond; or an equivalent thereof, oran N-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II) wherein W is O, S, SO, SO₂, CH₂, CHOH, CO, or NH; or anequivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II) wherein W is O, S, SO, or SO₂; or an equivalent thereof, oran N-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II) wherein W is O or S; or an equivalent thereof, or an N-oxidethereof, or a pharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II) wherein W is O; or an equivalent thereof, or an N-oxidethereof, or a pharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II) wherein W is CHOH or CO; or an equivalent thereof, or anN-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be directed to a compound of formula(I) or (II) wherein W is CO; or an equivalent thereof, or an N-oxidethereof, or a pharmaceutically acceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) wherein: U¹ is N; wherein U² is C—R²; wherein U³ is N—R⁶ or S;wherein U⁴ is C—R⁶; wherein each R⁶ is independently hydrogen or methyl;and wherein R² is as defined above for a compound of Formula (I); or anequivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) wherein U¹ is N; wherein U² is C—R²; wherein U³ is N—H; wherein U⁴is C—R⁶, wherein R⁶ is hydrogen or methyl; and wherein R² is as definedabove for a compound of Formula (I); or an equivalent thereof, or anN-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be directed to a compound of formula(I) wherein U¹ is N; wherein U² is C—R²; wherein U³ is N—H; wherein U⁴is C—H; wherein R² is as defined above for a compound of Formula (I); oran equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) wherein U¹ is N; wherein U² is C—R²; wherein U³ is N—H; wherein U⁴is C—CH₃; wherein R² is as defined above for a compound of Formula (I);or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) wherein U¹ is N; wherein U² is N—R⁶; wherein U³ is C—R²; wherein U⁴is C—R⁶, wherein each R⁶ is independently hydrogen or methyl; andwherein R² is as defined above for a compound of Formula (I); or anequivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) wherein U¹ is N; wherein U² is N—H; wherein U³ is C—R²; wherein U⁴is C—R⁶, wherein R⁶ is hydrogen or methyl; and wherein R² is as definedabove for a compound of Formula (I); or an equivalent thereof, or anN-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be directed to a compound of formula(I) wherein U¹ is N; wherein U² is N—H; wherein U³ is C—R²; wherein U⁴is C—H; wherein R² is as defined above for a compound of Formula (I); oran equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) wherein U¹ is N; wherein U² is N—H; wherein U³ is C—R²; wherein U⁴is C—CH₃; wherein R² is as defined above for a compound of Formula (I);or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be directed to a compound of formula(I) wherein each of Y¹, Y², and Y³ is C—H; or an equivalent thereof, oran N-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be directed to a compound of formula(I) wherein each of Y¹ and Y² is C—H and Y³ is N; or an equivalentthereof, or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of: 2-phenyl-5-(2-phenyl-1H-imidazol-4-yl)pyrimidine;5-(2-(2-fluorophenyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(2-(3-fluorophenyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(2-(4-fluorophenyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;2-phenyl-5-(2-(pyridin-2-yl)-1H-imidazol-4-yl)pyrimidine;2-phenyl-5-(2-(pyridin-3-yl)-1H-imidazol-4-yl)pyrimidine;2-phenyl-5-(2-(pyridin-4-yl)-1H-imidazol-4-yl)pyrimidine;5-(2-benzyl-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(2-(2-fluorobenzyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(2-(3-fluorobenzyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(2-(4-fluorobenzyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;2-phenyl-5-(2-(pyridin-2-ylmethyl)-1H-imidazol-4-yl)pyrimidine;2-phenyl-5-(2-(pyridin-3-ylmethyl)-1H-imidazol-4-yl)pyrimidine;2-phenyl-5-(2-(pyridin-4-ylmethyl)-1H-imidazol-4-yl)pyrimidine;5-(5-methyl-2-phenyl-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(1-methyl-2-phenyl-1H-imidazol-5-yl)-2-phenylpyrimidine;5-(1-methyl-2-phenyl-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(5-methyl-2-(pyridin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(1-methyl-2-(pyridin-3-yl)-1H-imidazol-5-yl)-2-phenylpyrimidine; and5-(1-methyl-2-(pyridin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine; or anequivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of:2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine;5-(2-(1-benzylpiperidin-4-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(2-(1-benzylpiperidin-4-yl)-5-methyl-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(2-(1-benzylpiperidin-4-yl)-1-methyl-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(2-(1-benzylpiperidin-4-yl)-1-methyl-1H-imidazol-5-yl)-2-phenylpyrimidine;5-(2-(1-(cyclopropylmethyl)piperidin-4-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;3-(4-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyridazine;5-(2-(1-(1-methyl-1H-tetrazol-5-yl)piperidin-4-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;N-methyl-4-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide; ethyl4-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate;tert-butyl4-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate;1-(4-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one;2-phenyl-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-1H-imidazol-4-yl)pyrimidine;2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)pyrimidine;(R)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)pyrimidine;(S)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)pyrimidine;5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(R)-5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(R)-5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(2-(1-benzylpiperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(R)-5-(2-(1-benzylpiperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(S)-5-(2-(1-benzylpiperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;N-methyl-3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide;(R)—N-methyl-3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide;(S)—N-methyl-3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide;N-cyclopropyl-3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide;(R)—N-cyclopropyl-3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide;(S)—N-cyclopropyl-3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide;cyclopropyl(3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)methanone;(R)-cyclopropyl(3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)methanone;(S)-cyclopropyl(3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)methanone;5-(2-(1-(cyclopropylmethyl)piperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(R)-5-(2-(1-(cyclopropylmethyl)piperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(S)-5-(2-(1-(cyclopropylmethyl)piperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-2-yl)-1H-imidazol-4-yl)pyrimidine;(S)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-2-yl)-1H-imidazol-4-yl)pyrimidine;and(R)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-2-yl)-1H-imidazol-4-yl)pyrimidine;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of:2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)pyrimidine;(R)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)pyrimidine;(S)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)pyrimidine;5-(2-(1-benzylpyrrolidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(R)-5-(2-(1-benzylpyrrolidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(S)-5-(2-(1-benzylpyrrolidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;ethyl3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;(R)-ethyl3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;(S)-ethyl3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;tert-butyl3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;(R)-tert-butyl3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;(S)-tert-butyl3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;N-methyl-3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxamide;(R)—N-methyl-3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxamide;(S)—N-methyl-3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxamide;2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)pyrimidine;(S)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)pyrimidine;(R)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)pyrimidine;2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-1H-imidazol-4-yl)pyrimidine;5-(2-(1-benzylazetidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;1-(3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)azetidin-1-yl)butan-1-one;5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(R)-5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(S)-5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(2-(1-benzylpyrrolidin-3-yl)-5-methyl-1H-imidazol-4-yl)-2-phenylpyrimidine;(R)-5-(2-(1-benzylpyrrolidin-3-yl)-5-methyl-1H-imidazol-4-yl)-2-phenylpyrimidine;and(S)-5-(2-(1-benzylpyrrolidin-3-yl)-5-methyl-1H-imidazol-4-yl)-2-phenylpyrimidine;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of: (E)-2-phenyl-5-(2-styryl-1H-imidazol-4-yl)pyrimidine;(E)-5-(2-(2-fluorostyryl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(E)-5-(2-(3-fluorostyryl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(E)-5-(2-(4-fluorostyryl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(E)-2-phenyl-5-(2-(2-(pyridin-2-yl)vinyl)-1H-imidazol-4-yl)pyrimidine;(E)-2-phenyl-5-(2-(2-(pyridin-3-yl)vinyl)-1H-imidazol-4-yl)pyrimidine;(E)-2-phenyl-5-(2-(2-(pyridin-4-yl)vinyl)-1H-imidazol-4-yl)pyrimidine;(E)-2-(3-fluorophenyl)-5-(5-methyl-2-(2-(pyridin-3-yl)vinyl)-1H-imidazol-4-yl)pyrimidine;and(E)-2-(3-fluorophenyl)-5-(1-methyl-2-(2-(pyridin-3-yl)vinyl)-1H-imidazol-4-yl)pyrimidine;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of: 5-(2-phenethyl-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(2-(2-fluorophenethyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(2-(3-fluorophenethyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(2-(4-fluorophenethyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;2-phenyl-5-(2-(2-(pyridin-2-yl)ethyl)-1H-imidazol-4-yl)pyrimidine;2-phenyl-5-(2-(2-(pyridin-3-yl)ethyl)-1H-imidazol-4-yl)pyrimidine;2-phenyl-5-(2-(2-(pyridin-4-yl)ethyl)-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(5-methyl-2-(2-(pyridin-3-yl)ethyl)-1H-imidazol-4-yl)pyridine;and5-(1-methyl-2-(2-(pyridin-3-yl)ethyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of(E)-5-(2-(2-(1-benzylpiperidin-4-yl)vinyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(E)-2-phenyl-5-(2-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)vinyl)-1H-imidazol-4-yl)pyrimidine;(S,E)-2-phenyl-5-(2-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)vinyl)-1H-imidazol-4-yl)pyrimidine;(R,E)-2-phenyl-5-(2-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)vinyl)-1H-imidazol-4-yl)pyrimidine;(E)-2-phenyl-5-(2-(2-(1-propylpiperidin-2-yl)vinyl)-1H-imidazol-4-yl)pyrimidine;(S,E)-2-phenyl-5-(2-(2-(1-propylpiperidin-2-yl)vinyl)-1H-imidazol-4-yl)pyrimidine;(R,E)-2-phenyl-5-(2-(2-(1-propylpiperidin-2-yl)vinyl)-1H-imidazol-4-yl)pyrimidine;(E)-3-(2-(4-(2-(3-fluorophenyl)pyrimidin-5-yl)-5-methyl-1H-imidazol-2-yl)vinyl)-N-methylpyrrolidine-1-carboxamide;and(E)-5-(2-(2-(1-(cyclopropylmethyl)pyrrolidin-2-yl)vinyl)-1-methyl-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of:5-(2-(2-(1-benzylpiperidin-4-yl)ethyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;2-phenyl-5-(2-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)ethyl)-1H-imidazol-4-yl)pyrimidine;(S)-2-phenyl-5-(2-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)ethyl)-1H-imidazol-4-yl)pyrimidine;(R)-2-phenyl-5-(2-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)ethyl)-1H-imidazol-4-yl)pyrimidine;5-(2-(2-(1-isobutylpiperidin-2-yl)ethyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(S)-5-(2-(2-(1-isobutylpiperidin-2-yl)ethyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;(R)-5-(2-(2-(1-isobutylpiperidin-2-yl)ethyl)-1H-imidazol-4-yl)-2-phenylpyrimidine;ethyl 3-(2-(4-(2-(3-fluorophenyl)pyrimidin-5-yl)-5-methyl-1H-imidazol-2-yl)ethyl)pyrrolidine-1-carboxylate; and1-(2-(2-(4-(6-(3-fluorophenyl)pyridin-3-yl)-1-methyl-1H-imidazol-2-yl)ethyl)pyrrolidin-1-yl)butan-1-one;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of: 2-phenyl-5-(2-phenyl-1H-imidazol-4-yl)pyridine;5-(2-(2-fluorophenyl)-1H-imidazol-4-yl)-2-phenylpyridine;5-(2-(3-fluorophenyl)-1H-imidazol-4-yl)-2-phenylpyridine;5-(2-(4-fluorophenyl)-1H-imidazol-4-yl)-2-phenylpyridine;2-phenyl-5-(2-(pyridin-2-yl)-1H-imidazol-4-yl)pyridine;2-phenyl-5-(2-(pyridin-3-yl)-1H-imidazol-4-yl)pyridine;2-phenyl-5-(2-(pyridin-4-yl)-1H-imidazol-4-yl)pyridine;5-(2-benzyl-1H-imidazol-4-yl)-2-phenylpyridin;5-(2-(2-fluorobenzyl)-1H-imidazol-4-yl)-2-phenylpyridine;5-(2-(3-fluorobenzyl)-1H-imidazol-4-yl)-2-phenylpyridine;5-(2-(4-fluorobenzyl)-1H-imidazol-4-yl)-2-phenylpyridine;2-phenyl-5-(2-(pyridin-2-ylmethyl)-1H-imidazol-4-yl)pyridine;2-phenyl-5-(2-(pyridin-3-ylmethyl)-1H-imidazol-4-yl)pyridine;2-phenyl-5-(2-(pyridin-4-ylmethyl)-1H-imidazol-4-yl)pyridine;5-(5-methyl-2-phenyl-1H-imidazol-4-yl)-2-phenylpyridine;5-(1-methyl-2-phenyl-1H-imidazol-5-yl)-2-phenylpyridine;5-(1-methyl-2-phenyl-1H-imidazol-4-yl)-2-phenylpyridine;5-(5-methyl-2-(pyridin-3-yl)-1H-imidazol-4-yl)-2-phenylpyridine;5-(1-methyl-2-(pyridin-3-yl)-1H-imidazol-5-yl)-2-phenylpyridine; and5-(1-methyl-2-(pyridin-3-yl)-1H-imidazol-4-yl)-2-phenylpyridine; or anequivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of:2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-imidazol-4-yl)pyridine;5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-imidazol-4-yl)-2-phenylpyridine;5-(2-(1-benzylpiperidin-4-yl)-1H-imidazol-4-yl)-2-phenylpyridine;5-(2-(1-benzylpiperidin-4-yl)-5-methyl-1H-imidazol-4-yl)-2-phenylpyridine;5-(2-(1-benzylpiperidin-4-yl)-1-methyl-1H-imidazol-4-yl)-2-phenylpyridine;5-(2-(1-benzylpiperidin-4-yl)-1-methyl-1H-imidazol-5-yl)-2-phenylpyridine;5-(2-(1-(cyclopropylmethyl)piperidin-4-yl)-1H-imidazol-4-yl)-2-phenylpyridine;3-(4-(4-(6-phenylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyridazine;5-(2-(1-(1-methyl-1H-tetrazol-5-yl)piperidin-4-yl)-1H-imidazol-4-yl)-2-phenylpyridine;N-methyl-4-(4-(6-phenylpyridin-3-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide;ethyl4-(4-(6-phenylpyridin-3-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate;1-(4-(4-(6-phenylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one;2-phenyl-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-1H-imidazol-4-yl)pyridine;2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)pyridine;5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyridine;(R)-5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyridine;(S)-5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyridine;(R)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)pyridine;(S)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)pyridine;5-(2-(1-benzylpiperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyridine;(R)-5-(2-(1-benzylpiperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyridine;(S)-5-(2-(1-benzylpiperidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyridine;N-cyclopropyl-3-(4-(6-phenylpyridin-3-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide;(R)—N-cyclopropyl-3-(4-(6-phenylpyridin-3-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide;(S)—N-cyclopropyl-3-(4-(6-phenylpyridin-3-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide;2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-2-yl)-1H-imidazol-4-yl)pyridine;(S)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-2-yl)-1H-imidazol-4-yl)pyridine;and(R)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-2-yl)-1H-imidazol-4-yl)pyridine;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of:2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)pyridine;(R)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)pyridine;(S)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)pyridine;5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyridine;(R)-5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyridine;(S)-5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyridine;5-(2-(1-benzylpyrrolidin-3-yl)-5-methyl-1H-imidazol-4-yl)-2-phenylpyridine;5-(2-(1-benzylpyrrolidin-3-yl)-1-methyl-1H-imidazol-4-yl)-2-phenylpyridine;5-(2-(1-benzylpyrrolidin-3-yl)-1-methyl-1H-imidazol-5-yl)-2-phenylpyridine;(R)-5-(2-(1-benzylpyrrolidin-3-yl)-5-methyl-1H-imidazol-4-yl)-2-phenylpyridine;(R)-5-(2-(1-benzylpyrrolidin-3-yl)-1-methyl-1H-imidazol-4-yl)-2-phenylpyridine;(R)-5-(2-(1-benzylpyrrolidin-3-yl)-1-methyl-1H-imidazol-5-yl)-2-phenylpyridine;(S)-5-(2-(1-benzylpyrrolidin-3-yl)-5-methyl-1H-imidazol-4-yl)-2-phenylpyridine;(S)-5-(2-(1-benzylpyrrolidin-3-yl)-1-methyl-1H-imidazol-4-yl)-2-phenylpyridine;(S)-5-(2-(1-benzylpyrrolidin-3-yl)-1-methyl-1H-imidazol-5-yl)-2-phenylpyridine;ethyl3-(4-(6-phenylpyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;(R)-ethyl3-(4-(6-phenylpyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;(S)-ethyl3-(4-(6-phenylpyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;N-methyl-3-(4-(6-phenylpyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxamide;(R)—N-methyl-3-(4-(6-phenylpyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxamide;(S)—N-methyl-3-(4-(6-phenylpyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxamide;2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)pyridine;(S)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)pyridine;(R)-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)pyridine;2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-1H-imidazol-4-yl)pyridine;5-(2-(1-benzylazetidin-3-yl)-1H-imidazol-4-yl)-2-phenylpyridine; and1-(3-(4-(6-phenylpyridin-3-yl)-1H-imidazol-2-yl)azetidin-1-yl)butan-1-one;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of:2-(3-fluorophenyl)-5-(2-phenyl-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(2-(2-fluorophenyl)-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(2-(3-fluorophenyl)-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(2-(4-fluorophenyl)-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(2-(pyridin-2-yl)-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(2-(pyridin-3-yl)-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(2-(pyridin-4-yl)-1H-imidazol-4-yl)pyrimidine;5-(2-benzyl-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyrimidine;5-(2-(2-fluorobenzyl)-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyrimidine;5-(2-(3-fluorobenzyl)-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyrimidine;5-(2-(4-fluorobenzyl)-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyrimidine;2-(3-fluorophenyl)-5-(2-(pyridin-2-ylmethyl)-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(2-(pyridin-3-ylmethyl)-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(2-(pyridin-4-ylmethyl)-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(5-methyl-2-phenyl-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(1-methyl-2-phenyl-1H-imidazol-5-yl)pyrimidine;2-(3-fluorophenyl)-5-(1-methyl-2-phenyl-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(5-methyl-2-(pyridin-3-yl)-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(1-methyl-2-(pyridin-3-yl)-1H-imidazol-5-yl)pyrimidine;and2-(3-fluorophenyl)-5-(1-methyl-2-(pyridin-3-yl)-1H-imidazol-4-yl)pyrimidine;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of:2-(3-fluorophenyl)-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-imidazol-4-yl)pyridine;5-(2-(1-benzylpiperidin-4-yl)-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyrimidine;5-(2-(1-benzylpiperidin-4-yl)-5-methyl-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;5-(2-(1-benzylpiperidin-4-yl)-1-methyl-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;5-(2-(1-benzylpiperidin-4-yl)-1-methyl-1H-imidazol-5-yl)-2-(3-fluorophenyl)pyridine;5-(2-(1-(cyclopropylmethyl)piperidin-4-yl)-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyrimidine;3-(4-(4-(2-(3-fluorophenyl)pyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyridazine;2-(3-fluorophenyl)-5-(2-(1-(1-methyl-1H-tetrazol-5-yl)piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine;4-(4-(2-(3-fluorophenyl)pyrimidin-5-yl)-1H-imidazol-2-yl)-N-methylpiperidine-1-carboxamide;ethyl4-(4-(6-(3-fluorophenyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate;1-(4-(4-(6-(3-fluorophenyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one;2-(3-fluorophenyl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)pyridine;(R)-2-(3-fluorophenyl)-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)pyridine;(S)-2-(3-fluorophenyl)-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-4-yl)pyridine;5-(2-(1-benzylpiperidin-3-yl)-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;(R)-5-(2-(1-benzylpiperidin-3-yl)-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;(S)-5-(2-(1-benzylpiperidin-3-yl)-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;N-cyclopropyl-3-(4-(6-(3-fluorophenyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide;(R)—N-cyclopropyl-3-(4-(6-(3-fluorophenyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide;(S)—N-cyclopropyl-3-(4-(6-(3-fluorophenyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide;2-(3-fluorophenyl)-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-2-yl)-1H-imidazol-4-yl)pyridine;(S)-2-(3-fluorophenyl)-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-2-yl)-1H-imidazol-4-yl)pyridine;and(R)-2-(3-fluorophenyl)-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-2-yl)-1H-imidazol-4-yl)pyridine;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of:2-(3-fluorophenyl)-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)pyridine;(R)-2-(3-fluorophenyl)-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)pyridine;(S)-2-(3-fluorophenyl)-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-1H-imidazol-4-yl)pyridine;5-(2-(1-benzylpyrrolidin-3-yl)-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;(R)-5-(2-(1-benzylpyrrolidin-3-yl)-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;(S)-5-(2-(1-benzylpyrrolidin-3-yl)-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;5-(2-(1-benzylpyrrolidin-3-yl)-5-methyl-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;(R)-5-(2-(1-benzylpyrrolidin-3-yl)-5-methyl-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;(S)-5-(2-(1-benzylpyrrolidin-3-yl)-5-methyl-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;5-(2-(1-benzylpyrrolidin-3-yl)-1-methyl-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;(R)-5-(2-(1-benzylpyrrolidin-3-yl)-1-methyl-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;(S)-5-(2-(1-benzylpyrrolidin-3-yl)-1-methyl-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;5-(2-(1-benzylpyrrolidin-3-yl)-1-methyl-1H-imidazol-5-yl)-2-(3-fluorophenyl)pyridine;(R)-5-(2-(1-benzylpyrrolidin-3-yl)-1-methyl-1H-imidazol-5-yl)-2-(3-fluorophenyl)pyridine;(S)-5-(2-(1-benzylpyrrolidin-3-yl)-1-methyl-1H-imidazol-5-yl)-2-(3-fluorophenyl)pyridine;ethyl3-(4-(2-(3-fluorophenyl)pyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;(R)-ethyl3-(4-(2-(3-fluorophenyl)pyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;(S)-ethyl3-(4-(2-(3-fluorophenyl)pyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;3-(4-(6-(3-fluorophenyl)pyridin-3-yl)-1H-imidazol-2-yl)-N-methylpyrrolidine-1-carboxamide;(R)-3-(4-(6-(3-fluorophenyl)pyridin-3-yl)-1H-imidazol-2-yl)-N-methylpyrrolidine-1-carboxamide;(S)-3-(4-(6-(3-fluorophenyl)pyridin-3-yl)-1H-imidazol-2-yl)-N-methylpyrrolidine-1-carboxamide;2-(3-fluorophenyl)-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)pyridine;(S)-2-(3-fluorophenyl)-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)pyridine;(R)-2-(3-fluorophenyl)-5-(2-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)pyridine;2-(3-fluorophenyl)-5-(2-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-1H-imidazol-4-yl)pyridine;5-(2-(1-benzylazetidin-3-yl)-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;5-(2-(1-benzylazetidin-3-yl)-5-methyl-1H-imidazol-4-yl)-2-(3-fluorophenyl)pyridine;and1-(3-(4-(6-(3-fluorophenyl)pyridin-3-yl)-1H-imidazol-2-yl)azetidin-1-yl)butan-1-one;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of: 2-phenoxy-5-(2-phenyl-1H-imidazol-4-yl)pyrimidine;5-(2-(3-fluorophenyl)-1H-imidazol-4-yl)-2-phenoxypyrimidine;2-phenoxy-5-(2-(pyridin-3-yl)-1H-imidazol-4-yl)pyrimidine;5-(5-methyl-2-(pyridin-3-yl)-1H-imidazol-4-yl)-2-phenoxypyrimidine;5-(1-methyl-2-(pyridin-3-yl)-1H-imidazol-4-yl)-2-phenoxypyrimidine;5-(1-methyl-2-(pyridin-3-yl)-1H-imidazol-5-yl)-2-phenoxypyrimidine;5-(2-(1-benzylpiperidin-4-yl)-5-methyl-1H-imidazol-4-yl)-2-phenoxypyrimidine;5-(2-(1-benzylpiperidin-4-yl)-1-methyl-1H-imidazol-4-yl)-2-phenoxypyrimidine;5-(2-(1-benzylpiperidin-4-yl)-1-methyl-1H-imidazol-5-yl)-2-phenoxypyrimidine;5-(5-methyl-2-(pyridin-3-yl)-1H-imidazol-4-yl)-2-phenoxypyridine;5-(1-methyl-2-(pyridin-3-yl)-1H-imidazol-4-yl)-2-phenoxypyridine;5-(1-methyl-2-(pyridin-3-yl)-1H-imidazol-5-yl)-2-phenoxypyridine;5-(2-(1-benzylpiperidin-4-yl)-5-methyl-1H-imidazol-4-yl)-2-phenoxypyridine;5-(2-(1-benzylpiperidin-4-yl)-1-methyl-1H-imidazol-4-yl)-2-phenoxypyridine;5-(2-(1-benzylpiperidin-4-yl)-1-methyl-1H-imidazol-5-yl)-2-phenoxypyridine;5-(2-benzyl-1H-imidazol-4-yl)-2-phenoxypyrimidine;2-phenoxy-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine;5-(2-(1-benzylpiperidin-4-yl)-1H-imidazol-4-yl)-2-phenoxypyrimidine;5-(2-(1-(cyclopropylmethyl)piperidin-4-yl)-1H-imidazol-4-yl)-2-phenoxypyrimidine;3-(4-(4-(2-phenoxypyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyridazine;5-(2-(1-(1-methyl-1H-tetrazol-5-yl)piperidin-4-yl)-1H-imidazol-4-yl)-2-phenoxypyrimidine;N-methyl-4-(4-(2-phenoxypyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide;2-phenoxy-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-1H-imidazol-4-yl)pyrimidine;ethyl3-(4-(2-phenoxypyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;(R)-ethyl3-(4-(2-phenoxypyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;(S)-ethyl3-(4-(2-phenoxypyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate;5-(5-methyl-2-phenyl-1H-imidazol-4-yl)-2-phenoxypyrimidine;5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-imidazol-4-yl)-2-phenoxypyrimidine;and 5-(5-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-imidazol-4-yl)-2-phenoxypyridine; or an equivalent thereof, or anN-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of: 2-phenyl-5-(5-phenyl-1H-pyrazol-3-yl)pyrimidine;5-(5-(3-fluorophenyl)-1H-pyrazol-3-yl)-2-phenylpyrimidine;2-phenyl-5-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)pyrimidine;5-(5-benzyl-1H-pyrazol-3-yl)-2-phenylpyrimidine;2-phenyl-5-(5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-3-yl)pyrimidine;5-(5-(1-benzylpiperidin-4-yl)-1H-pyrazol-3-yl)-2-phenylpyrimidine;5-(5-(1-(cyclopropylmethyl)piperidin-4-yl)-1H-pyrazol-3-yl)-2-phenylpyrimidine;3-(4-(3-(2-phenylpyrimidin-5-yl)-1H-pyrazol-5-yl)piperidin-1-yl)pyridazine;5-(5-(1-(1-methyl-1H-tetrazol-5-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-2-phenylpyrimidine;N-methyl-4-(3-(2-phenylpyrimidin-5-yl)-1H-pyrazol-5-yl)piperidine-1-carboxamide;2-phenyl-5-(5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-1H-pyrazol-3-yl)pyrimidine;ethyl3-(3-(2-phenylpyrimidin-5-yl)-1H-pyrazol-5-yl)pyrrolidine-1-carboxylate;(R)-ethyl3-(3-(2-phenylpyrimidin-5-yl)-1H-pyrazol-5-yl)pyrrolidine-1-carboxylate;(S)-ethyl3-(3-(2-phenylpyrimidin-5-yl)-1H-pyrazol-5-yl)pyrrolidine-1-carboxylate;and 5-(4-methyl-5-phenyl-1H-pyrazol-3-yl)-2-phenylpyrimidine; or anequivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of: 3-(2-phenylpyrimidin-5-yl)-1H-pyrazole-5-carboxylic acid;methyl 3-(2-phenylpyrimidin-5-yl)-1H-pyrazole-5-carboxylate; ethyl3-(2-phenylpyrimidin-5-yl)-1H-pyrazole-5-carboxylate;(4-methylpiperazin-1-yl)(3-(2-phenylpyrimidin-5-yl)-1H-pyrazol-5-yl)methanone;ethyl 3-(6-phenylpyridin-3-yl)-1H-pyrazole-5-carboxylate;(4-methylpiperazin-1-yl)(3-(6-phenylpyridin-3-yl)-1H-pyrazol-5-yl)methanone;ethyl 3-(2-(3-fluorophenyl)pyrimidin-5-yl)-1 H-pyrazole-5-carboxylate;(3-(2-(3-fluorophenyl)pyrimidin-5-yl)-1H-pyrazol-5-yl)(4-methylpiperazin-1-yl)methanone;ethyl 3-(6-(3-fluorophenyl)pyridin-3-yl)-1 H-pyrazole-5-carboxylate;(3-(6-(3-fluorophenyl)pyridin-3-yl)-1H-pyrazol-5-yl)(4-methylpiperazin-1-yl)methanone;ethyl 4-methyl-3-(2-phenylpyrimidin-5-yl)-1H-pyrazole-5-carboxylate;(4-methyl-3-(2-phenylpyrimidin-5-yl)-1H-pyrazol-5-yl)(4-methylpiperazin-1-yl)methanone;ethyl 1-methyl-3-(2-phenylpyrimidin-5-yl)-1H-pyrazole-5-carboxylate;(1-methyl-3-(2-phenylpyrimidin-5-yl)-1H-pyrazol-5-yl)(4-methylpiperazin-1-yl)methanone;ethyl 1-methyl-5-(2-phenylpyrimidin-5-yl)-1H-pyrazole-3-carboxylate;(1-methyl-5-(2-phenylpyrimidin-5-yl)-1H-pyrazol-3-yl)(4-methylpiperazin-1-yl)methanone;methyl 3-(2-phenoxypyrimidin-5-yl)-1H-pyrazole-5-carboxylate; ethyl3-(2-phenoxypyrimidin-5-yl)-1H-pyrazole-5-carboxylate;(3-(2-benzoylpyrimidin-5-yl)-1H-pyrazol-5-yl)(4-methylpiperazin-1-yl)methanone;(3-(6-benzoylpyridin-3-yl)-1H-pyrazol-5-yl)(4-methylpiperazin-1-yl)methanone;and(4-methylpiperazin-1-yl)(3-(2-phenoxypyrimidin-5-yl)-1H-pyrazol-5-yl)methanone;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of:2-phenyl-5-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine;5-(1-(1-benzylpiperidin-4-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine;5-(1-(1-benzylpiperidin-4-yl)-1H-imidazol-4-yl)-2-phenylpyridine;5-(1-(1-benzylpiperidin-4-yl)-1H-imidazol-4-yl)-2-phenoxypyrimidine;5-(1-(1-benzylpiperidin-4-yl)-1H-imidazol-4-yl)-2-phenoxypyridine;2-phenyl-5-(1-(pyridin-3-ylmethyl)-1H-imidazol-4-yl)pyrimidine;5-(1-benzyl-1H-imidazol-4-yl)-2-phenylpyrimidine; tert-butyl4-(2-methyl-4-(2-phenylpyrimidin-5-yl)-1H-imidazol-1-yl)piperidine-1-carboxylate;5-(1-benzyl-2-methyl-1H-imidazol-4-yl)-2-phenylpyrimidine;2-phenyl-5-(1-(pyridin-3-yl)-1H-imidazol-4-yl)pyrimidine;2-(3-fluorophenyl)-5-(1-(pyridin-3-ylmethyl)-1H-imidazol-4-yl)pyrimidine;andN-cyclopropyl-3-(4-(2-(3-fluorophenyl)pyrimidin-5-yl)-1H-imidazol-1-yl)pyrrolidine-1-carboxamide;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of:2-phenyl-5-(5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyrimidine;2-phenyl-5-(5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyridine;5-(1-methyl-5-(pyridin-3-yl)-1H-1,2,4-triazol-3-yl)-2-phenylpyrimidine;5-(1-methyl-5-(pyridin-3-yl)-1H-1,2,4-triazol-3-yl)-2-phenylpyridine;2-phenoxy-5-(5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyrimidine;2-phenoxy-5-(5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyridine;2-phenyl-5-(5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-4H-1,2,4-triazol-3-yl)pyrimidine;and2-phenyl-5-(5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-4H-1,2,4-triazol-3-yl)pyridine;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of:(5-(2-(3-fluorophenyl)-1H-imidazol-4-yl)pyrimidin-2-yl)(phenyl)methanone;phenyl(5-(2-(pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2-yl)methanone;(5-(2-(1-benzylpiperidin-4-yl)-1H-imidazol-4-yl)pyrimidin-2-yl)(phenyl)methanone;(5-(2-(3-fluorophenyl)-5-methyl-1H-imidazol-4-yl)pyrimidin-2-yl)(phenyl)methanone;(5-(5-methyl-2-(pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2-yl)(phenyl)methanone;(5-(2-(1-benzylpiperidin-4-yl)-5-methyl-1H-imidazol-4-yl)pyrimidin-2-yl)(phenyl)methanone;(5-(2-(3-fluorophenyl)-1-methyl-1H-imidazol-4-yl)pyrimidin-2-yl)(phenyl)methanone;(5-(1-methyl-2-(pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2-yl)(phenyl)methanone;and(5-(2-(1-benzylpiperidin-4-yl)-1-methyl-1H-imidazol-4-yl)pyrimidin-2-yl)(phenyl)methanone;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

Another exemplary embodiment may be a compound selected from the groupconsisting of:4-methyl-2-phenyl-5-(2-(pyridin-3-yl)-1H-imidazol-5-yl)thiazole;2-(3-fluorophenyl)-4-methyl-5-(2-(pyridin-3-yl)-1H-imidazol-5-yl)thiazole;4-methyl-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-imidazol-5-yl)thiazole;4-methyl-2-phenyl-5-(2-(1-(pyridazin-3-yl)piperidin-4-yl)-1H-imidazol-5-yl)thiazole;4-methyl-2-phenyl-5-(2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-imidazol-5-yl)thiazole;and5-(2-(1-benzylpyrrolidin-3-yl)-1H-imidazol-5-yl)-4-methyl-2-phenylthiazole;or an equivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof.

The exemplary embodiments may also be directed to a method of preventingor treating a disease or condition mediated at least in part byprostaglandin D₂ produced by H-PGDS, in a subject in need of suchtreatment, comprising administering to the subject a therapeuticallyeffective amount of a compound of formula (I) or (II), or an equivalentthereof, or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof; the use of a compound of formula (I) or (II), or anequivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, for the manufacture of a medicamentfor preventing or treating a disease or condition mediated at least inpart by prostaglandin D₂ produced by H-PGDS; a compound of formula (I)or (II), or an equivalent thereof, or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof, for use as amedicament; a compound of formula (I) or (II), or an equivalent thereof,or an N-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof, for use in the prevention or treatment of a disease orcondition mediated at least in part by prostaglandin D₂ produced byH-PGDS; a pharmaceutical composition comprising a compound of formula(I) or (II), or an equivalent thereof, or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable excipient; a pharmaceutical composition forthe prevention and treatment of a disease or condition mediated at leastin part by prostaglandin D₂ produced by H-PGDS comprising a compound offormula (I) or (II), or an equivalent thereof, or an N-oxide thereof, ora pharmaceutically acceptable salt or solvate thereof.

The diseases and conditions mediated at least in part by prostaglandinD₂ produced by H-PGDS may include allergy and allergic inflammation.Diseases and conditions of this kind may be allergic respiratoryconditions such as allergic rhinitis, nasal congestion, rhinorrhea,perennial rhinitis, nasal inflammation, asthma of all types, chronicobstructive pulmonary disease (COPD), chronic or acutebronchoconstriction, chronic bronchitis, small airways obstruction,emphysema, chronic eosinophilic pneumonia, adult respiratory distresssyndrome, exacerbation of airways hyper-reactivity consequent to otherdrug therapy, airways disease that may be associated with pulmonaryhypertension, acute lung injury, bronchiectasis, sinusitis, allergicconjunctivitis, or atopic dermatitis, particularly asthma or chronicobstructive pulmonary disease.

Types of asthma may include atopic asthma, non-atopic asthma, allergicasthma, atopic bronchial IgE-mediated asthma, bronchial asthma,essential asthma, true asthma, intrinsic asthma caused bypathophysiologic disturbances, extrinsic asthma caused by environmentalfactors, essential asthma of unknown or inapparent cause, bronchiticasthma, emphysematous asthma, exercise-induced asthma, exertion asthma,allergen-induced asthma, cold air induced asthma, occupational asthma,infective asthma caused by bacterial, fungal, protozoal, or viralinfection, non-allergic asthma, incipient asthma, wheezy infantsyndrome, and bronchiolytis.

Included in the use of the compounds of formula (I) and (II) for thetreatment of asthma, may be palliative treatment for the symptoms andconditions of asthma such as wheezing, coughing, shortness of breath,tightness in the chest, shallow or fast breathing, nasal flaring(nostril size increases with breathing), retractions (neck area andbetween or below the ribs moves inward with breathing), cyanosis (grayor bluish tint to skin, beginning around the mouth), runny or stuffynose, and headache.

Other diseases and conditions that may be mediated, at least in part, byprostaglandin D2 produced by H-PGDS are arthritis (especially rheumatoidarthritis), irritable bowel diseases (such as Crohns disease andulcerative colitis), irritable bowel syndrome, inflammatory pain,chronic pain, muscular necrosis (such as Duchenne muscular dystrophy),skin inflammation and irritation (such as eczema), niacin-induced skinflushing, cealic type disease (e.g. as a result of lactose intolerance),wound healing, and dermal scarring (Kapoor, M., Kojima, F., Yang, L.,and Crofford, L. J. Prostaglandins Leukot. Essent. Fatty Acids, 76(2),2007, 103-112). Chronic pain conditions may include neuropathic painconditions (such as painful diabetic neuropathy and postherpeticneuralgia), carpel tunnel syndrome, back pain, headache, cancer pain,arthritic pain and chronic post-surgical pain.

The exemplary embodiments may also be directed to any of the uses,methods, or compositions as defined above wherein the compound offormula (I) or (II), or an equivalent thereof, or an N-oxide thereof, ora pharmaceutically acceptable salt or solvate thereof, that is used incombination with another pharmacologically active compound. Specificcombinations useful according to the exemplary embodiments may includecombinations comprising a compound of formula (I) or (II), or anequivalent thereof, or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof., and (i) a glucocorticosteroid orDAGR (dissociated agonist of the corticoid receptor); (ii) a β₂ agonist,an example of which is a long-acting β₂ agonist; (iii) a muscarinic M3receptor antagonist or anticholinergic agent; (iv) a histamine receptorantagonist or inverse agonist, which may be an H1 or an H3 antagonist orinverse agonist; (v) a 5-lipoxygenase inhibitor; (vi) a thromboxaneinhibitor; (vii) an LTD₄ inhibitor; (viii) a kinase inhibitor; or (ix) avaccine. Generally, the compounds of the combination may be administeredtogether as a formulation in association with one or morepharmaceutically acceptable excipients.

Besides being useful for human treatment, compounds of formula (I) or(II) may also be useful for veterinary treatment of companion animals,exotic animals, and farm animals.

When used in the present application, the following abbreviations havethe meaning set out below: Ac is acetyl; ACN is acetonitrile; BBr₃ isboron tribromide; Bn is benzyl; BnNH₂ is benzylamine; BSA is bovineserum albumin; CH₂Cl₂ is dichloromethane; CHCl₃ is chloroform; CDCl₃ isdeuterochloroform; dba is dibenzylideneacetone; DCC isN,N′-dicyclohexylcarbodiimide; DCM is dichloromethane; DME is1,2-dimethoxyethane; DMF is N,N-dimethylformamide; DMSO is dimethylsulfoxide; DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene; EDC/EDAC isN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; EDTA isethylenediaminetetraacetic acid; EIA is enzyme immunoassay; Et is ethyl;Et₃N is triethylamine; HCl is hydrogen chloride; HOBt is1-hydroxybenzotriazole; Me is methyl; MTBE is methyl tert-butyl ether;NaOMe is sodium methoxide; NMP is 1-methyl-2-pyrrolidinone; PGrepresents a chemical protecting group; Ph is phenyl; Pd(PPh₃)₄ istetrakis(triphenylphosphine)palladium; PhB(OH)₂ is benzeneboronic acid,also known as phenylboronic acid; PhMe is toluene; rt is roomtemperature; TBAB is tetrabutylammonium bromide; t-Bu is tert-butyl; THFis tetrahydrofuran; TLC is thin layer chromatography; and Tris-HCl is2-amino-2-(hydroxymethyl)-1,3-propanediol hydrochloride.

Unless otherwise defined herein, scientific and technical terms used inconnection with the exemplary embodiments shall have the meanings thatare commonly understood by those of ordinary skill in the art.

Further, unless otherwise required by context, singular terms shallinclude pluralities and plural terms shall include the singular.Generally, nomenclature used in connection with, and techniques ofchemistry and molecular biology described herein are those well knownand commonly used in the art.

The phrase “therapeutically effective” is intended to qualify the amountof compound or pharmaceutical composition, or the combined amount ofactive ingredients in the case of combination therapy. This amount orcombined amount may achieve the goal of treating the relevant condition.

The term “treatment,” as used herein to describe the exemplaryembodiments and unless otherwise qualified, means administration of thecompound, pharmaceutical composition, or combination to effectpreventative, palliative, supportive, restorative, or curativetreatment. The term treatment encompasses any objective or subjectiveimprovement in a subject with respect to a relevant condition ordisease.

The term “preventative treatment,” as used herein to describe theexemplary embodiments, means that the compound, pharmaceuticalcomposition, or combination may be administered to a subject to inhibitor stop the relevant condition from occurring in a subject, particularlyin a subject or member of a population that may be significantlypredisposed to the relevant condition.

The term “palliative treatment,” as used herein to describe theexemplary embodiments, means that the compound, pharmaceuticalcomposition, or combination may be administered to a subject to remedysigns and/or symptoms of a condition, without necessarily modifying theprogression of, or underlying etiology of, the relevant condition.

The term “supportive treatment,” as used herein to describe theexemplary embodiments, means that the compound, pharmaceuticalcomposition, or combination may be administered to a subject as part ofa regimen of therapy, but that such therapy is not limited toadministration of the compound, pharmaceutical composition, orcombination. Unless otherwise expressly stated, supportive treatment mayembrace preventative, palliative, restorative, or curative treatment,particularly when the compounds or pharmaceutical compositions arecombined with another component of supportive therapy.

The term “restorative treatment,” as used herein to describe theexemplary embodiments, means that the compound, pharmaceuticalcomposition, or combination may be administered to a subject to modifythe underlying progression or etiology of a condition. Non-limitingexamples include an increase in forced expiratory volume in one second(FEV 1) for lung disorders, inhibition of progressive nerve destruction,reduction of biomarkers associated and correlated with diseases ordisorders, a reduction in relapses, improvement in quality of life, andthe like.

The term “curative treatment,” as used herein to describe the exemplaryembodiments, means that the compound, pharmaceutical composition, orcombination may be administered to a subject for the purpose of bringingthe disease or disorder into complete remission, or that the disease ordisorder in undetectable after such treatment.

The term “alkyl,” alone or in combination, means an acyclic radical,linear or branched, preferably containing from 1 to about 6 carbonatoms. Examples of such radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, heptyl, octyl, and the like. Where no specific substitution isspecified, alkyl radicals may be optionally substituted with groupsconsisting of hydroxy, sulfhydryl, methoxy, ethoxy, amino, cyano,chloro, and fluoro. Examples of such substituted alkyl radicals includechloroethyl, hydroxyethyl, cyanobutyl, aminopentyl and the like.

The carbon atom content of various hydrocarbon-containing moieties isindicated by a prefix designating a lower and upper number of carbonatoms in the moiety, that is, the prefix C_(i)-C_(j) indicates a moietyof the integer “i” to the integer “j” carbon atoms, inclusive. Thus, forexample, ‘(C₁-C₆)-alkyl’ refers to alkyl of one to six carbon atoms,inclusive.

The terms “hydroxy” and “hydroxyl,” as used herein, mean an OH radical.

The term “sulfhydryl,” as used herein, means an SH radical.

The term “oxo” means a doubly bonded oxygen.

The term “alkoxy” means a radical comprising an alkyl radical that isbonded to an oxygen atom, such as a methoxy radical. Preferred alkoxyradicals have one to about six carbon atoms. Examples of such radicalsinclude methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy.

The term “aryl” means a fully unsaturated mono- or multi-ring cycloalkylhaving a cyclic array of p-orbitals containing 4n+2 electrons,including, but not limited to, substituted or unsubstituted phenyl,naphthyl, or anthracenyl optionally fused to a carbocyclic radicalwherein aryl may be optionally substituted with one or more substituentsfrom the group consisting of halo, methoxy, ethoxy, (C₁-C₆)-alkyl,phenyl, O-phenyl, cyano, nitro, hydroxyl, sulfhydryl, ortrifluoromethyl.

The term “halo,” as used herein, means one of the following groupconsisting of fluoro, chloro, bromo, or iodo.

The terms “heterocycle”, “heterocyclic ring system,” and “heterocyclyl”refer to a saturated or unsaturated mono- or multi-ring cycloalkylwherein one or more carbon atoms is replaced by N, S, or O. The terms“heterocycle”, “heterocyclic ring system,” and “heterocyclyl” includefully saturated ring structures such as azetidinyl, piperazinyl,dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl,pyrrolidinyl, piperidinyl, thiazolidinyl, and others. The terms“heterocycle”, “heterocyclic ring system,” and “heterocyclyl” alsoinclude partially unsaturated ring structures such as dihydrofuranyl,pyrazolinyl, imidazolinyl, pyrrolinyl, chromanyl, dihydrothiphenyl, andothers.

A preferred non-aromatic heterocyclic group is a five- or six-memberedsaturated or partially unsaturated heterocyclic group containing one ortwo nitrogen or oxygen groups, optionally substituted by one or more of(C₁-C₆)-alkyl, (C₁-C₆)-fluoroalkyl, (C₃-C₆)-cycloalkyl,hydroxy(C₃-C₆)-cycloalkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, halo, oxo,hydroxyl, —(CH₂)_(p)OH, —OR⁸, —(CH₂)_(p)OR⁸, sulfhydryl, —(CH₂)_(p)SH,—SR⁸, —(CH₂)_(p)SR⁸, —NR⁸R⁹, —(CH₂)_(p)NR⁸R⁹, —CO₂R⁸, —(CH₂)_(p)CO₂R⁸,—CONR⁸R⁹, —(CH₂)_(p)CONR⁸R⁹, cyano, or —(CH₂)_(p)CN, wherein p is 1, 2,or 3 and each R⁸ and R⁹ is independently hydrogen or (C₁-C₆)-alkyloptionally substituted with —OH or —O—((C₁-C₆)-alkyl). Preferredexamples of non-aromatic heterocyclic groups include azetidinyl,pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl andmorpholinyl (optionally substituted as specified above).

The term “heteroaryl” refers to an aromatic heterocyclic group.Heteroaryl is preferably: (a) a five-membered aromatic heterocyclicgroup containing either (i) 1-4 nitrogen atoms or (ii) 0-3 nitrogenatoms and 1 oxygen or 1 sulfur atom; (b) a six-membered aromaticheterocyclic group containing 1-3 nitrogen atoms; (c) a nine-memberedbicyclic heterocyclic group containing either (i) 1-5 nitrogen atoms or(ii) 0-4 nitrogen atoms and 1 oxygen or 1 sulfur atom; or (d) aten-membered bicyclic aromatic heterocyclic group containing 1-6nitrogen atoms; each of said groups (a)-(d) being optionally substitutedby one or more of (C₁-C₆)-alkyl, (C₁-C₆)-fluoroalkyl,(C₃-C₆)-cycloalkyl, hydroxy(C₃-C₆)-cycloalkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, halo, oxo, hydroxyl, —(CH₂)_(p)OH, —OR⁸, —(CH₂)_(p)OR⁸,sulfhydryl, —(CH₂)_(p)SH, —SR⁸, —(CH₂)_(p)SR⁸, —NR⁸R⁹, —(CH₂)_(p)NR⁸R⁹,—CO₂R⁸, —(CH₂)_(p)CO₂R⁸, —CONR⁸R⁹, —(CH₂)_(p)CONR⁸R⁹, cyano, or—(CH₂)_(p)CN; wherein p is 1, 2, or 3 and each R⁸ and R⁹ isindependently hydrogen or (C₁-C₆)-alkyl optionally substituted with —OHor —O—((C₁-C₆)-alkyl). Examples of “heteroaryl” include pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, thionyl, furanyl, pyrrolyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl, optionallysubstituted as specified above.

In “heterocycle” or “heteroaryl,” the point of attachment to themolecule of interest may be at a heteroatom or elsewhere within thering.

The term “cycloalkyl” means a mono- or multi-ringed cycloalkyl whereineach ring contains three to ten carbon atoms, preferably three to sixcarbon atoms. “Cycloalkyl” is preferably a monocyclic cycloalkylcontaining from three to six carbon atoms. Examples include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

The symbols

denote the point of attachment of a substituent.

The wavy line attached to a double bond, as denoted here:

represents undefined double bond geometry, in that the symbol allows foreither cis (Z) or trans (E) geometry.

As used herein, the terms “co-administration,” “co-administered,” and“in combination with,” referring to a combination of a compound offormula (I) or (II) and one or more other therapeutic agents, isintended to mean, and does refer to and include the following:

-   -   (i) simultaneous administration of such combination of a        compound of formula (I) or (II) and a further therapeutic agent        to a patient in need of treatment, when such components are        formulated together into a single dosage form which releases        said components at substantially the same time to said patient;    -   (ii) substantially simultaneous administration of such a        combination of a compound of formula (I) or (II) and a further        therapeutic agent to a patient in need of treatment, when such        components are formulated apart from each other into separate        dosage forms which are taken at substantially the same time by        said patient, whereupon said components are released at        substantially the same time to said patient;    -   (iii) sequential administration of such a combination of a        compound of formula (I) or (II) and a further therapeutic agent        to a patient in need of treatment, when such components are        formulated apart from each other into separate dosage forms        which are taken at consecutive times by said patient with a        significant time interval between each administration, whereupon        said components are released at substantially different times to        said patient; and    -   (iv) sequential administration of such a combination of a        compound of formula (I) or (II) and a further therapeutic agent        to a patient in need of treatment, when such components are        formulated together into a single dosage form which releases        said components in a controlled manner whereupon they are        concurrently, consecutively, and/or overlappingly administered        at the same and/or different times by said patient, where each        part may be administered by either the same or different route.

The term “excipient” is used herein to describe any ingredient otherthan a compound of formula (I) or (II). The choice of excipient will toa large extent depend on factors such as the particular mode ofadministration, the effect of the excipient on solubility and stability,and the nature of the dosage form. The term “excipient” encompassesdiluents, carrier, or adjuvant.

Pharmaceutically acceptable salts of the compounds of formula (I) or(II) include the acid addition and base salts thereof.

Suitable acid addition salts are formed by acids which form non-toxicsalts. Examples include the acetate, adipate, aspartate, benzoate,besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate,citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate,gluconate, glucuronate, hexafluorophosphate, hibenzate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,isethionate, lactate, malate, maleate, malonate, mesylate,methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, propionate, pyroglutamate, saccharate, stearate, succinate,tannate, tartrate, tosylate, trifluoroacetate,naphthalene-1,5-disulfonic acid, and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminum, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine, and zinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulfate and hemicalcium salts. For a review on suitable salts, seeHandbook of Pharmaceutical Salts: Properties, Selection, and Use, byStahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of formulas (I) or (II)may be prepared by one or more of three methods:

-   -   (i) by reacting the compound of formula (I) or (II) with the        desired acid or base;    -   (ii) by removing an acid- or base-labile protecting group from a        suitable precursor of the compound of formula (I) or (II) or by        a ring-opening a suitable cyclic precursor, for example, a        lactone or lactam, using the desired acid or base; or    -   (iii) by converting one salt of the compound of formula (I)        or (II) to another by reaction with an appropriate acid or base        or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionization in theresulting salt may vary from completely ionized to almost non-ionized.

The compounds of formula (I) or (II) may also exist in unsolvated andsolvated forms. The term “solvate” is used herein to describe amolecular complex comprising the compound of formula (I) or (II), or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable solvent molecules, for example, ethanol orwater. The term “hydrate” is employed when said solvent is water.

Also included herein are multi-component complexes other than salts andsolvates wherein the compound of formula (I) or (II) and at least oneother component are present in stoichiometric or non-stoichiometricamounts.

The compounds of formula (I) or (II) may exist in a continuum of solidstates ranging from fully amorphous to fully crystalline.

The compounds of formula (I) or (II) may also exist in a mesomorphicstate (mesophase or liquid crystal) when subjected to suitableconditions. The mesomorphic state is intermediate between the truecrystalline state and the true liquid state (either melt or solution).

Hereinafter all references to compounds of formula (I) or (II) (alsoreferred to as compounds of the invention) include references to salts,solvates, multi-component complexes, and liquid crystals thereof and tosolvates, multi-component complexes, and liquid crystals of saltsthereof.

Also included herein are all polymorphs and crystal habits of compoundsof formula (I) or (II), prodrugs, and isomers thereof (includingoptical, geometric, and tautomeric isomers) and isotopically-labeledforms thereof.

As indicated, so-called ‘prodrugs’ of the compounds of formulas (I) and(II) are also within the scope of the invention. Thus certainderivatives of a compound of formula (I) or (II) which may have littleor no pharmacological activity themselves can, when administered into oronto the body, be converted into a compound of formula (I) or (II)having the desired activity, for example, by hydrolytic cleavage. Suchderivatives are referred to as ‘prodrugs.’ Further information on theuse of prodrugs may be found in Prodrugs as Novel Delivery Systems, Vol.14, ACS Symposium Series (T. Higuchi and W, Stella) and BioreversibleCarriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, AmericanPharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormulas (I) and (II) with certain moieties known to those skilled inthe art as ‘pro-moieties’ as described, for example, in Design ofProdrugs, by H. Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the exemplary embodimentsinclude:

-   -   (i) where a compound of formulas (I) or (II) contains a        carboxylic acid functionality (—CO₂H), an ester thereof; for        example, a compound wherein the hydrogen of the carboxylic acid        functionality of the compound of formula (I) or (II) is replaced        by (C₁-C₈)-alkyl;    -   (ii) where a compound of formulas (I) or (II) contains an        alcohol functionality (—OH), an ether thereof; for example, a        compound wherein the hydrogen of the alcohol functionality of        the compound of formula (I) or (II) is replaced by        (C₁-C₆)-alkanoyloxymethyl; and    -   (iii) where a compound of formulas (I) or (II) contains a        primary or secondary amino functionality (—NH₂ or —NHR where R        is not H), an amide thereof; for example, a compound wherein, as        the case may be, one or both hydrogens of the amino        functionality of the compound of formula (I) or (II) is/are        replaced by (C₁-C₁₀)-alkanoyl.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

Moreover, certain compounds of formulas (I) and (II) may themselves actas prodrugs of other compounds of formulas (I) and (II), respectively.

Also included within the scope of the invention are metabolites ofcompounds of formulas (I) and (II), that is, compounds formed in vivoupon administration of the drug.

Also included within the scope of the invention are compounds offormulas (I) and (II) that are all pharmaceutically acceptableisotopically labeled compounds of formulas (I) and (II) wherein one ormore atoms are replaced by atoms having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberwhich predominates in nature; for example, a compound of formula (I) or(II) for which one of the hydrogen atoms (¹H) is replaced with adeuterium (D, or ²H) or tritium (T, or ³H) isotope. Another exampleincludes a compound of formula (I) or (II) for which one of thecarbon-12 atoms (¹²C) is replaced with a carbon-14 (¹⁴C) isotope.Isotopically labeled compounds of formulas (I) and (II) can generally beprepared by conventional techniques known to those ordinarily skilled inthe art or by processes analogous to those described in the accompanyingExamples using an appropriately isotopically labeled reagent in place ofthe non-labeled reagent previously employed.

Also included within the scope of the invention are all stereoisomers,geometric isomers and tautomeric forms of the compounds of formulas (I)and (II), including compounds that exhibit more than one type ofisomerism, and mixtures of one or more thereof.

Cis/trans isomers may be separated by conventional techniques well knownto those ordinarily skilled in the art; for example, chromatography andfractional crystallization.

Conventional techniques for preparation and isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC). Alternatively, the racemate (or racemicprecursor) may be reacted with a suitable optically active compound, forexample, an alcohol, or, in the case where the compound of formula (I)or (II) contains an acidic or basic moiety, a base or an acid such as1-phenethylamine or tartaric acid. The resulting diastereomeric mixturemay be separated by chromatography and/or fractional crystallization andone or both of the diastereomers converted into the corresponding pureenantiomer(s) by means well known to those ordinarily skilled in theart.

Compounds of the exemplary embodiments of formulas (I) and (II) may beadministered orally, topically, transdermally, intranasally, byinhalation, directly into the bloodstream, into muscle, into an internalorgan, into the eye, into the ear, into the rectum, or by other means.

The compounds herein, their methods of preparation and their biologicalactivity will appear more clearly from the examination of the followingexamples that are presented as an illustration only and are not to beconsidered as limiting the invention in its scope. Compounds herein areidentified, for example, by the following analytical methods.

Mass spectra (MS) methods include positive electrospray ionization(ESI⁺), negative electrospray ionization (ESI⁻), positive atmosphericpressure chemical ionization (APCI⁺), or negative atmospheric pressurechemical ionization (APCI⁻).

400 MHz proton nuclear magnetic resonance spectra (¹H NMR) are recordedat ambient temperature using either a Bruker (300 MHz) or a Varian INOVA(400 MHz) nuclear magnetic resonance spectrometer. In the ¹H NMRchemical shifts (δ) are indicated in parts per million (ppm) withreference to tetramethylsilane (TMS) as the internal standard.

EXAMPLES

Examples 1-13, 32-33, and 44 are imidazole compounds that may beprepared according to the general synthetic route illustrated inScheme 1. Palladium-assisted coupling of 5-bromo-2-iodopyridine or5-bromo-2-iodopyrimidine (1) with the appropriate arylboronic acid (2)provided the corresponding 2-aryl-5-bromopyridine or2-aryl-5-bromopyrimidine intermediate (3). A subsequentpalladium-assisted coupling of an intermediate (3) with a1-benzyl-2-R²-substituted imidazole intermediate (4), which was preparedas illustrated in Scheme 2, provides the corresponding intermediategenerally illustrated as structure (5). Debenzylation catalyzed withpalladium on carbon affords the corresponding 5-(imidazol-4-yl)-pyridineor 5-(imidazol-4-yl)-pyrimidine (6).

For each of the examples and schemes below, temperatures, measurements,and time references are approximations and are not intended to belimited to the actual values listed.

H-PGDS H-PGDS FPBA Inhibitor EIA Ex. R⁶ R⁷ Y³ IC₅₀ (μM) IC₅₀ (μM) 1 H HN 0.25 0.012 2 H H CH 0.48 0.097 3 H Me N 0.625 0.25 4 Me H N 0.45 0.082

Example 1 Preparation of2-phenyl-5-(2-phenyl-1H-imidazol-5-yl)pyrimidine

Step A: Preparation of 5-bromo-2-phenylpyrimidine

A mixture consisting of 5-bromo-2-iodopyrimidine (Bridge Organics, 10.0g, 35.1 mmol), benzene boronic acid (Alfa Aesar, 4.25 g, 35.1 mmol),tetrakis(triphenylphosphine)palladium (Strem, 0.405 g, 0.351 mmol),toluene (150 mL), and a 2 M aqueous sodium carbonate solution (35 mL)was stirred at 115° C. (degrees Celsius) under a nitrogen atmosphere for16 hours. After cooling to room temperature, the mixture was partitionedbetween chloroform (250 mL) and brine (200 mL). The phases wereseparated and the organic phase was dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure to give an orange oil(9.1 g). The crude product was purified by flash silica columnchromatography. Elution through a 500-g Analogix® flash silica cartridgewith 100% hexanes afforded the title intermediate as a white solid (3.15g, 38% yield). R_(f) 0.69 with 9:1 v/v hexanes-ethyl acetate; ¹H-NMR(400 MHz; CDCl₃) δ 8.83 (s, 2H), 8.44-8.38 (m, 2H), 7.52-7.46 (m, 3H);MS (APCI⁺) m/z 236.9 (M+1).

Step B: Preparation of 1-benzyl-2-phenyl-1H-imidazole

To a mixture consisting of 2-phenylimidazole (TCI America, 3.0 g, 21mmol) and N,N-dimethylformamide (40 mL) was added 60% sodium hydride inmineral oil (0.92 g, 23 mmol). After stirring for one hour at roomtemperature, a solution consisting of benzyl bromide (Aldrich, 2.73 mL,22.9 mmol) in N,N-dimethylformamide (5 mL) was added dropwise whilestirring. After stirring at room temperatures for 12 hours the reactionwas complete as observed by TLC. The reaction mixture was partitionedbetween ethyl acetate (150 mL) and water (100 mL). The phases wereseparated and the organic layer was washed with brine (150 mL), and wassubsequently dried over anhydrous magnesium sulfate. Concentration underreduced pressure afforded the crude product as an orange oil (4.2 g).The product was purified by flash silica column chromatography. Elutionthrough a 80-g Silicycle® flash silica cartridge with gradient of 5% to30% ethyl acetate in hexanes afforded the title intermediate as acolorless oil (3.21 g, 66% yield). R_(f) 0.65 with 9:1 v/vdichloromethane-methanol; ¹H-NMR (400 MHz; CDCl₃) δ 7.57-7.53 (m, 2H),7.42-7.28 (m, 6H), 7.19 (d, 1H), 7.11-7.07 (m, 2H), 6.97 (d, 1H), 5.22(s, 2H).

Step C: Preparation of5-(1-benzyl-2-phenyl-1H-imidazol-5-yl)-2-phenylpyrimidine

To a mixture consisting of 5-bromo-2-phenylpyrimidine (1.2 g, 5.1 mmol),palladium (II) acetate (Strem, 0.048 g, 0.21 mmol),tris(2-furyl)phosphine (TCI America, 0.098 g, 0.43 mmol) and potassiumcarbonate (1.17 g, 8.52 mmol) was added a solution consisting of1-benzyl-2-phenyl-1H-imidazole (1.0 g, 4.3 mmol) inN,N-dimethylformamide (10 mL). The reaction mixture was brought toreflux at 140° C. (degrees Celsius) while under a N₂ atmosphere. Afterstirring for 16 hours at reflux the solution was cooled to roomtemperature. The reaction mixture was partitioned between ethyl acetate(250 mL) and saturated aqueous ammonium chloride (100 mL). The phaseswere separated and the organic layer was washed with brine (150 mL), andwas subsequently dried over anhydrous magnesium sulfate. Concentrationunder reduced pressure affords the crude product as an orange oil (0.658g). The product was purified by flash silica column chromatography.Elution through a 80-g Silicycle® flash silica cartridge with gradientof 5% to 30% ethyl acetate in hexanes afforded the title intermediate(0.495 g, 30% yield); R_(f) 0.38 with 1:1 v/v ethyl acetate-hexane;¹H-NMR (400 MHz; CDCl₃) δ 8.7 (s, 2H), 8.4 (m, 2H), 7.6 (m, 2H),7.5-7.25 (m, 10H), 6.9 (m, 2H), 5.32 (s, 2H); MS (ESI⁺) m/z 389.2 (M+1);H-PGDS FPBA IC₅₀: 15 μM.

Step D: Preparation of 2-phenyl-5-(2-phenyl-1H-imidazol-5-yl)pyrimidine

To a solution consisting of5-(1-benzyl-2-phenyl-1H-imidazol-5-yl)-2-phenylpyrimidine (0.495 g, 1.27mmol) in methanol (100 mL) was added ammonium formate (Aldrich, 0.804 g,12.7 mmol) and 10% palladium on carbon (Alfa Aesar, 0.500 g). Thereaction mixture was brought to reflux at 70° C. for 16 hours. Aftercooling the solution to room temperature, the crude reaction mixture wasfiltered over a bed of Celite, which was rinsed with additional methanol(300 mL). Concentration of the filtrate afforded an off-white solid. Theproduct was purified by flash silica column chromatography. Elutionthrough a 40-g Silicycle® flash silica cartridge with gradient of 100%dichloromethane to 5% methanol in dichloromethane afforded the titlecompound as a white solid (0.218 g, 57% yield); R_(f) 0.56 with 95:5 v/vdichloromethane-methanol; melting point 253° C.; ¹H-NMR (400 MHz;DMSO-d₆) δ 9.3 (s, 2H), 8.4 (m, 2H), 8.05 (m, 3H), 7.55-7.35 (m, 6H); MS(ESI⁺) m/z 299.1 (M+1); H-PGDS FPBA IC₅₀: 0.25 μM; H-PGDS inhibitor EIAIC₅₀: 0.012 μM.

Examples 2-12 were generally prepared according to the proceduresdescribed in Example 1. Exceptions are noted in each Example.

Example 2 Preparation of 2-phenyl-5-(2-phenyl-1H-imidazol-5-yl)pyridine

The title compound was prepared by the method described in Example 1,except that commercially available 2-iodo-5-bromopyridine was usedinstead of 2-iodo-5-bromopyrimidine in Step A; R_(f) 0.53 with 95:5 v/vdichloromethane-methanol; melting point 206° C.; ¹H-NMR (400 MHz;DMSO-d₆) δ 9.15 (s, 2H), 8.26 (dd, 2H), 8.14-7.94 (m, 5H), 7.52-7.34 (m,5H); MS (ESI⁺) m/z 298.1 (M+1); H-PGDS FPBA IC₅₀: 0.48 μM; H-PGDSinhibitor EIA IC₅₀: 0.097 μM.

Example 3 Preparation of5-(1-methyl-2-phenyl-1H-imidazol-5-yl)-2-phenylpyrimidine

The title compound was prepared by the method described in Example 1,Steps A-C, except that iodomethane was used instead of benzyl bromide inStep B; R_(f) 0.36 with 1:1 v/v ethyl acetate-hexane; melting point 211°C.; ¹H-NMR (400 MHz; DMSO-d₆) δ 9.17 (s, 2H), 8.41 (m, 2H), 7.75 (dd,2H), 7.6-7.27 (m, 7H); MS (ESI⁺) m/z 313.2 (M+1); H-PGDS FPBA IC₅₀:0.625 μM; H-PGDS inhibitor EIA IC₅₀: 0.25 μM.

Example 4 Preparation of5-(4-methyl-2-phenyl-1H-imidazol-5-yl)-2-phenylpyrimidine

The title compound was prepared by the method described in Example 1,except that commercially available 4-methyl-2-phenyl-1H-imidazole (TCIAmerica) was used instead of 2-phenylimidazole in Step B; R_(f) 0.73with 95:5 v/v dichloromethane-methanol; melting point 138° C.; ¹H-NMR(400 MHz; DMSO-d₆) δ 9.28 (s, 2H), 8.52-8.46 (m, 2H), 8.05 (d, 2H),7.64-7.52 (m, 5H), 7.44 (m, 1H), 2.64 (s, 3H); MS (ESI⁺) m/z 313.0(M+1); H-PGDS FPBA IC₅₀: 0.45 μM; H-PGDS inhibitor EIA IC₅₀: 0.082 μM.

H-PGDS H-PGDS Inhibitor FPBA EIA Ex. R² R¹ IC₅₀ (μM) IC₅₀ (μM) 5 H Ph 56 Ph 3-F—Ph 0.28 0.047 7 Ph 3,4- 3.5 diOMe—Ph 8 3-F—Ph Ph 0.188 0.004 92-pyridyl Ph 0.125 0.053 10 3-pyridyl Ph 0.079 0.021 11 3-pyridyl 3-F—Ph0.156 0.041 12 3-pyridyl 3-pyridyl 1.3 13 4-pyridyl Ph 0.125 0.075 14 BnPh 0.625 0.059 15

Ph 0.15 0.023 16

Ph 0.3 17

Ph 0.15 18

Ph 1.0 19

Ph 0.08 0.006 20

Ph 0.45 21

Ph 0.20 22

Ph 1.25 23

Ph 0.6 24

Ph 10 25

Ph 0.3 26

Ph 27

Ph 0.09 28

Ph 0.15 29

Ph 30

Ph 2 31

Ph

Example 5 Preparation of 5-(1H-imidazol-5-yl)-2-phenylpyrimidine

The title compound was prepared by the method described in Example 1,except that imidazole (Aldrich) was used instead of 2-phenylimidazole inStep B; R_(f) 0.13 with 95:5 v/v dichloromethane-methanol; melting point216° C.; ¹H-NMR (400 MHz; DMSO-d₆) δ 9.32 (s, 2H), 8.50-8.43 (m, 2H),7.99 (s, 1H), 7.91 (s, 1H), 7.62-7.55 (m, 3H); MS (ESI⁺) m/z 223.0(M+1); H-PGDS FPBA IC₅₀: 5 μM.

Example 6 Preparation of2-(3-fluorophenyl)-5-(2-phenyl-1H-imidazol-5-yl)pyrimidine

The title compound was prepared by the method described in Example 1,except that commercially available 3-fluorobenzene boronic acid was usedinstead of benzeneboronic acid in Step A; R_(f) 0.61 with 95:5 v/vdichloromethane-methanol; melting point 240° C.; ¹H-NMR (400 MHz; CDCl₃)δ 8.97 (s, 2H), 7.99 (d, 1H), 7.90-7.85 (m, 1H), 7.80-7.75 (m, 2H), 7.31(s, 1H), 7.22-7.07 (m, 4H), 6.89 (dt, 1H); MS (ESI⁺) m/z 317.1 (M+1);H-PGDS FPBA IC₅₀: 0.28 μM; H-PGDS inhibitor EIA IC₅₀: 0.047 μM.

Example 7 Preparation of2-(3,4-dimethoxyphenyl)-5-(2-phenyl-1H-imidazol-5-yl)pyrimidine

The title compound was prepared by the method described in Example 1,except that commercially available 3,4-dimethoxybenzene boronic acid wasused instead of benzeneboronic acid in Step A; R_(f) 0.45 with 95:5 v/vdichloromethane-methanol; melting point 231° C.; ¹H-NMR (400 MHz;DMSO-d₆) δ 9.23 (s, 2H), 8.06-7.94 (m, 5H), 7.48 (m, 2H), 7.38 (m, 1H),7.08 (d, 1H), 3.84 (s, 3H), 3.82 (s, 3H); MS (ESI⁺) m/z 359.1 (M+1);H-PGDS FPBA IC₅₀: 3.5 μM.

Example 8 Preparation of5-(2-(3-fluorophenyl)-1H-imidazol-5-yl)-2-phenylpyrimidine

Step A: Preparation of 2-(3-fluorophenyl)-1H-imidazole

In a flask containing 3-fluorobenzonitrile (Matrix Scientific, 3.0 g, 25mmol) was added methanol (30 mL) and sodium methoxide (Aldrich, 25% bywt. in methanol, 2.83 mL, 12.4 mmol). The reaction mixture was stirredfor 1.5 hours and aminoacetaldehyde dimethyl acetal (Alfa Aesar, 2.60 g,24.8 mmol) and acetic acid (2.83 mL, 49.5 mmol) were subsequently addedand the solution was heated at reflux for one hour. After cooling toroom temperature, methanol (25 mL) and 6 N HCl (8 mL) was added and thesolution was heated at reflux for 16 hours. After cooling the solutionto room temperature the residue was taken up in a 1:1 mixture (v/v) ofwater and ethyl acetate (50 mL). The aqueous layer was separated and thepH of this solution was adjusted to pH 9 with 2 N NaOH, upon which awhite precipitate formed in solution. The solid was collected byfiltration and dried under high vacuum to provide2-(3-fluorophenyl)-1H-imidazole as an off-white solid (1.67 g, 41%yield, MS (ESI⁺) m/z 163.1 (M+1).

Step B: Preparation of 1-benzyl-2-(3-fluorophenyl)-1H-imidazole

To a mixture consisting of 2-(3-fluorophenyl)-1H-imidazole (0.80 g, 4.9mmol) and N,N-dimethylformamide (10 mL) was added 60% sodium hydride inmineral oil (0.22 g, 5.4 mmol). After stirring for one hour at roomtemperature, a solution consisting of benzyl bromide (Aldrich, 0.65 mL,5.4 mmol) in N,N-dimethylformamide (5 mL) was added dropwise whilestirring. After stirring at room temperatures for 12 hours the reactionwas complete as observed by TLC. The reaction mixture was partitionedbetween ethyl acetate (150 mL) and water (100 mL). The phases wereseparated and the organic layer was washed with brine (100 mL), and wassubsequently dried over anhydrous magnesium sulfate. Concentration underreduced pressure afforded the crude product as a yellow oil. The productwas purified by flash silica column chromatography. Elution through a40-g Silicycle® flash silica cartridge with gradient of 10% to 30% ethylacetate in hexane, and subsequently 5% methanol in dichloromethaneafforded the title intermediate as a colorless oil (0.408 g, 32% yield);R_(f) 0.45 with 95:5 v/v dichloromethane-methanol; (ESI⁺) m/z 253.1(M+1).

Step C: Preparation of5-(2-(3-fluorophenyl)-1H-imidazol-5-yl)-2-phenylpyrimidine

The title compound was prepared by the method described in Example 1,except that 1-benzyl-2-(3-fluorophenyl)-1H-imidazole was used instead of1-benzyl-2-phenyl-1H-imidazole in Step C; R_(f) 0.55 with 95:5 v/vdichloromethane-methanol; melting point 221° C.; ¹H-NMR (400 MHz;DMSO-d₆) δ 9.31 (s, 2H), 8.44-8.37 (m, 2H), 8.14-8.06 (m, 1H), 7.88-7.77(m, 2H), 7.58-7.48 (m, 4H), 7.23 (dt, 1H); MS (ESI⁺) m/z 317.1 (M+1);H-PGDS FPBA IC₅₀: 0.188 μM; H-PGDS inhibitor EIA IC₅₀: 0.004 μM.

Example 9 Preparation of2-phenyl-5-(2-(pyridin-2-yl)-1H-imidazol-5-yl)pyrimidine

The title compound was prepared by the method described in Example 1,except that 2-(1-benzyl-1H-imidazol-2-yl)pyridine (prepared according toExample 8, Step A, except that commercially available 2-cyanopyridinewas used instead of 3-fluorobenzonitrile) was used instead of1-benzyl-2-phenyl-1H-imidazole in Step C; R_(f) 0.43 with 95:5 v/vdichloromethane-methanol; melting point 262° C.; ¹H-NMR (400 MHz;DMSO-d₆) δ 9.33 (s, 2H), 8.63 (d, 1H), 8.43-8.37 (m, 2H), 8.16 (d, 1H),8.06 (d, 1H), 7.94 (dt, 1H), 7.54-7.49 (m, 3H), 7.43-7.39 (m, 1H); MS(ESI⁺) m/z 300.1 (M+1); H-PGDS FPBA IC₅₀: 0.125 μM; H-PGDS inhibitor EIAIC₅₀: 0.053 μM.

Example 10 Preparation of2-phenyl-5-(2-(pyridin-3-yl)-1H-imidazol-5-yl)pyrimidine

The title compound was prepared by the method described in Example 1,except that 3-(1-benzyl-1H-imidazol-2-yl)pyridine was used instead of1-benzyl-2-phenyl-1H-imidazole in Step C.3-(1-Benzyl-1H-imidazol-2-yl)pyridine was prepared by the methoddescribed in Example 8, Steps A and B except the commercially available3-cyanopyridine was used instead of 3-fluorobenzonitrile; R_(f) 0.25with 95:5 v/v dichloromethane-methanol; melting point 308° C.; ¹H-NMR(400 MHz; DMSO-d₆) δ 9.32 (s, 2H), 9.20 (d, 1H), 8.58 (dd, 1H),8.44-8.31 (m, 3H), 8.12 (m, 1H), 7.57-7.46 (m, 4H); MS (ESI⁺) m/z 300.1(M+1); H-PGDS FPBA IC₅₀: 0.079 μM; H-PGDS inhibitor EIA IC₅₀: 0.021 μM.

Example 11 Preparation of2-(3-fluorophenyl)-5-(2-(pyridin-3-yl)-1H-imidazol-5-yl)pyrimidine

The title compound was prepared by the method described in Example 1,except that (i) commercially available 3-fluorobenzene boronic acid wasused instead of benzeneboronic acid in Step A, and (ii)3-(1-benzyl-1H-imidazol-2-yl)pyridine (prepared according to the methoddescribed in Example 8, Step A, except that commercially available3-cyanopyridine was used instead of 3-fluorobenzonitrile) was used inplace of the 1-benzyl-2-phenyl-1H-imidazole in Step C; R_(f) 0.35 with95:5 v/v dichloromethane-methanol; melting point 309° C.; ¹H-NMR (400MHz; DMSO-d₆) δ 9.40 (s, 2H), 9.27 (d, 1H), 8.64 (dd, 1H), 8.40 (dt,1H), 8.31 (dd, 1H), 8.23 (bs, 1H), 8.18-8.13 (m, 1H), 7.66-7.55 (m, 3H),7.42 (dt, 1H); MS (ESI⁺) m/z 318.0 (M+1); H-PGDS FPBA IC₅₀: 0.156 μM;H-PGDS inhibitor EIA IC₅₀: 0.041 μM.

Example 12 Preparation of2-(pyridin-3-yl)-5-(2-(pyridin-3-yl)-1H-imidazol-5-yl)pyrimidine

The title compound was prepared by the method described in Example 1,except that (i) commercially available 3-pyridyl boronic acid was usedinstead of benzene boronic acid in Step A, and (ii)3-(1-benzyl-1H-imidazol-2-yl)pyridine was used instead of1-benzyl-2-phenyl-1H-imidazole in Step C.3-(1-Benzyl-1H-imidazol-2-yl)pyridine was prepared by the methoddescribed in Example 8, Steps A and B except the commercially available3-cyanopyridine was used instead of 3-fluorobenzonitrile; R_(f) 0.35with 92.5:7.5 v/v dichloromethane-methanol; melting point 299° C.;¹H-NMR (400 MHz; DMSO-d₆) δ 9.52 (s, 1H), 9.35 (s, 2H), 9.21 (s, 1H),8.72-8.65 (m, 2H), 8.60-8.56 (m, 1H), 8.37-8.32 (m, 1H), 8.15 (s, 1H),7.58-7.50 (m, 2H); LC/MS (ESI⁺) m/z 301.1 (M+1); H-PGDS FPBA IC₅₀: 1.3μM.

Example 13 Preparation of2-phenyl-5-(2-(pyridin-4-yl)-1H-imidazol-5-yl)pyrimidine

The title compound was prepared by the method described in Example 1,except that 4-(1-benzyl-1H-imidazol-2-yl)pyridine (prepared according toExample 8, Step A, except that commercially available 4-cyanopyridinewas used instead of 3-fluorobenzonitrile) was used in place of the1-benzyl-2-phenyl-1H-imidazole in Step C; R_(f) 0.26 with 95:5 v/vdichloromethane-methanol; melting point 300° C.; ¹H-NMR (400 MHz;DMSO-d₆) δ 9.40 (s, 2H), 8.73 (d, 2H), 8.50-8.45 (m, 2H), 8.25 (bs, 1H),8.00 (d, 2H), 7.62-7.55 (m, 4H); MS (ESI⁺) m/z 300.0 (M+1); H-PGDS FPBAIC₅₀: 0.125 μM; H-PGDS inhibitor EIA IC₅₀: 0.075 μM.

Imidazole compounds of the exemplary embodiments may also be preparedusing the general alternative synthetic route illustrated in Scheme 3.Examples 14-31 are imidazole compounds of the exemplary embodiments thatwere prepared at least in part according to the route illustrated inScheme 3. Bromopyridines and bromopyrimidines of general structure 3 maybe heated with tributyl(1-ethoxyvinyl)stannane in the presence of apalladium catalyst, such as palladium(II) acetate and a ligand, such astriphenylphosphine, in an organic solvent, such as 1,4-dioxane, to formthe corresponding ketones of general structure 11, as shown in Scheme 3.Bromination of ketone 11 with a bromination reagent such astetrabutylammonium tribromide provides the corresponding α-bromoketoneof general structure 12. Reaction of an α-bromoketone 12 with acarboxylic acid bearing a desired R² group or R² group precursor in thepresence of a base, such as cesium carbonate in a solvent, such astetrahydrofuran (THF) or N,N-dimethylformamide (DMF), provides thecorresponding ester-ketone intermediate with the general structure 13.Reaction of an ester-ketone 13 with ammonium acetate in a solvent, suchas toluene, with heating, affords the corresponding imidazole compoundof general structure 14.

An alternative method, described in Scheme 4, may also be used toprepare ketone intermediates with the general structure 11. Aspects ofthis methodology may be found in patent application publication WO2009/080523 (Scheme 2, Steps I and J) and in Han, Ki-Jong; Kim, Misoo;Letters in Organic Chemistry, 2007, 4(1), 20-22. Starting from aprepared or commercially available carboxylic acid 15, reaction withtriphosgene in the presence of excess amine base forms an activatedcarbonyl intermediate, which is subsequently reacted withN,O-dimethylhydroxylamine hydrochloride to provide the Weinreb amideintermediate 16. Reaction of the Weinreb amide with methylmagnesiumchloride in THF provides the corresponding acetophenone 11 with goodoverall yield. Other methods for preparing ketones of this general typeare known to those ordinarily skilled in the art.

Example 14 Preparation of5-(2-benzyl-1H-imidazol-5-yl)-2-phenylpyrimidine

Step A: Preparation of 1-(2-phenylpyrimidin-5-yl)ethanone

A stirring mixture consisting of palladium(II) acetate (215 mg, 0.32mmol) and triphenylphosphine (335 mg, 1.28 mmol) in 1,4-dioxane (25 mL)was heated at 80° C. for 30 minutes. The dark reaction mixture wascooled to room temperature, and to this reaction mixture was added asolution consisting of 5-bromo-2-phenylpyrimidine (Example 1A, 3.0 g, 13mmol) and tributyl(1-ethoxyvinyl)tin (4.74 mL, 14.0 mmol) in 1,4-dioxane(63 mL). The reaction mixture was stirred and heated at 75° C. overnightand was subsequently cooled to room temperature. The reaction progresswas monitored by thin layer chromatography (95:5 v/v hexanes-ethylacetate) until completion. The reaction mixture was treated with 1 Nhydrochloric acid (19 mL) for one hour at room temperature and pouredinto a saturated aqueous sodium bicarbonate solution. The organicmaterial was extracted two times with a mixture of ethyl acetate andhexanes, and the combined organic phase was washed sequentially withwater and brine, and was dried over anhydrous magnesium sulfate,filtered through a well packed pad of magnesium sulfate, andconcentrated under reduced pressure. The residue was dissolved indichloromethane (30 mL) and diluted with hexanes (30 mL). The resultingprecipitate was filtered to give the title intermediate (872 mg). Thefiltrate was applied to a 80-g silica column eluted with 1:1:9 v/v/vethyl acetate-dichloromethane-hexanes to afford 1.01 g of additionaltitle intermediate (1.88 g total, 74%); R_(f) 0.23 with 9:1 v/vhexanes-ethyl acetate solvent system; ¹H-NMR (400 MHz; DMSO-d₆) δ 9.4(s, 2H), 8.45-8.50 (m, 2H), 7.5-7.7 (m, 3H), 2.68 (s, 3H); MS (ESI⁺) m/z199 (M+1).

Alternative preparation of 1-(2-phenylpyrimidin-5-yl)ethanone Step i:Preparation of N-methoxy-N-methyl-2-phenylpyrimidine-5-carboxamide

To an ice-cooled solution (0° C.) consisting of2-phenylpyrimidine-5-carboxylic acid (prepared according to WO2007/041634 A1 Example 1, 2.10 g, 10.5 mmol) in dichloromethane (40 mL)was added triphosgene (1.55 g, 5.25 mmol) and triethylamine (7.3 mL,52.45 mmol). Upon addition of triethylamine a yellow precipitate formedin solution. After stirring for five minutes in the ice bath,N,O-dimethylhydroxylamine hydrochloride (1.02 g, 10.5 mmol) was addedand the solution was allowed to slowly warm to room temperature over 30minutes. The reaction was complete after stirring for three hours atroom temperature. The crude solution was filtered and washed with excessdichloromethane. The filtrate was concentrated under reduced pressure toafford an orange solid. The crude product was purified by flash silicacolumn chromatography. Elution through a 40-g Silicycle® flash silicacartridge with 10-30% ethyl acetate in hexanes afforded the titleintermediate as a colorless oil (1.85 g, 72% yield); R_(f) 0.48 with 1:1v/v hexanes-ethyl acetate; ¹H-NMR (400 MHz; CDCl₃) δ 9.20 (s, 2H), 8.50(dd, 2H), 7.55 (m, 3H), 3.62 (s, 3H), 3.42 (s, 3H); MS (APCI⁺) m/z 244.0(M+1).

Step ii: Preparation of 1-(2-phenylpyrimidin-5-yl)ethanone

A solution consisting ofN-methoxy-N-methyl-2-phenylpyrimidine-5-carboxamide (Step I, 1.80 g,7.39 mmol) in anhydrous THF (20 mL) was cooled in a −60° C. bath(ethanol, CO₂(s)). Methylmagnesium chloride (Aldrich, 3.0 M in THF, 2.75mL, 8.14 mmol) was subsequently added dropwise to the reaction mixture.The reaction mixture was stirred for 30 minutes in the −60° C. bath andwas subsequently allowed to warm to room temperature over one hour. Thecrude reaction mixture was then poured into a separatory funnel thatcontained diethyl ether (200 mL) and saturated ammonium chloride (150mL). The organic layer was separated and the aqueous layer was washedagain with diethyl ether (100 mL). The combined organic layer was driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure to afford a white solid as the crude product. The crude solidwas triturated with a hexane-ethyl acetate (9:1 v/v) mixture (20 mL).The precipitate in solution was filtered to afford the title compound asa white solid (1.15 g, 78% yield); R_(f) 0.72 with 1:1 v/v hexanes-ethylacetate; ¹H-NMR (400 MHz; CDCl₃) δ 9.25 (s, 2H), 8.53 (dd, 2H), 7.58 (m,3H), 2.63 (s, 3H); MS (APCI⁺) m/z 199.0 (M+1).

Step B: Preparation of 2-bromo-1-(2-phenylpyrimidin-5-yl)ethanone

To a solution consisting of 1-(2-phenylpyrimidin-5-yl)ethanone (Step A,700 mg, 3.5 mmol) in dichloromethane (25 mL) was addedtetrabutylammonium tribromide (1.87 g, 3.90 mmol). The reaction mixturewas sealed with a screw top and warmed at 40° C. for 5 hours and allowedto cool to room temperature over a weekend. The pale yellow precipitateformed was collected on a filter and washed with 1:1dichloromethane-hexane to afford the title intermediate (770 mg, 79%);R_(f) 0.31 with 9:1 v/v hexanes-ethyl acetate; MS (ESI⁺) m/z 279, 277(M+1, Br isotopes).

Step C: Preparation of 5-(2-benzyl-1H-imidazol-5-yl)-2-phenylpyrimidine

To a solution consisting of phenylacetic acid (27 mg, 0.20 mmol) andcesium carbonate (117 mg, 0.360 mmol) in tetrahydrofuran (1.5 mL) atroom temperature was added 2-bromo-1-(2-phenylpyrimidin-5-yl)ethanone(Step B, 50 mg, 0.18 mmol). The reaction mixture was heated at 40° C.for one hour and cooled to room temperature. To the mixture was addedwater (10 mL) with vigorous stirring and the precipitate was filtered,washed with water, and dried on the suction filter to provide2-oxo-2-(2-phenylpyrimidin-5-yl)ethyl 2-phenylacetate as a tan solid(34.5 mg, 57% yield) as an isolated intermediate. The tan solid wasdissolved in toluene (4 mL) and freshly prepared ammonium acetate undertoluene (300 mg wet with toluene) was added and the mixture was stirredvigorously and heated in a capped vial at 112° C. overnight. The brownreaction mixture was poured into aqueous sodium bicarbonate andextracted twice with ethyl acetate. The combined organic phase was driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure to dryness. The brown solid was dissolved indichloromethane and chromatographed on a 4 g silica column eluted with1:4:5 to 1:6:3 dichloromethane-ethyl acetate-hexane to afford the titlecompound as a tan solid; R_(f) 0.08 with 6:4 v/v hexanes-ethyl acetateand R_(f) 0.61 with 3:7 v/v hexanes-ethyl acetate; melting point 235°C.; ¹H-NMR (400 MHz; DMSO-d₆) δ 9.21 (s, 2H), 8.3-8.5 (m, 2H), 7.82 (d,1H), 7.5-7.6 (m, 3H), 7.2-7.4 (m, 5H), 4.08 (s, 2H); MS (ESI⁺) m/z 313(M+1); H-PGDS FPBA IC₅₀: 0.625 μM; H-PGDS inhibitor EIA IC₅₀: 0.059 μM.

Example 15 Preparation of(E)-2-phenyl-5-(2-(2-(pyridin-3-yl)vinyl)-1H-imidazol-5-yl)pyrimidine

To a solution consisting of trans-3-(3-pyridyl)acrylic acid (30 mg, 0.20mmol) and cesium carbonate (117 mg, 0.360 mmol) in tetrahydrofuran (1.5mL) was added 2-bromo-1-(2-phenylpyrimidin-5-yl)ethanone (Example 14,Step B, 50 mg, 0.18 mmol). The reaction mixture was warmed at 40° C. for1.5 hours, cooled to room temperature, and stirred vigorously whilewater (15 mL) was added quickly. The precipitate was filtered, washedwith water, and dried in high vacuum to give crude material (32.5 mg)that was dissolved in of toluene (4 mL). To this solution was addedfreshly prepared ammonium acetate under toluene (400 mg wet with tolueneand acetic acid). The reaction mixture was heated at 112° C. overnightand subsequently cooled to room temperature. The brown precipitate wasfiltered and the mother liquor was concentrated under reduced pressureand chromatographed on silica (4 g) eluted with ethyl acetate. Theproduct was purified by crystallization from methanol and water toafford the title compound (5.4 mg, 18% yield) as a tan crystalline-likesolid; R_(f) 0.35 with 3:97 v/v ethanol-ethyl acetate; melting point258° C.; ¹H-NMR (400 MHz; DMSO-d₆) δ 9.29 (s, 2H), 8.78 (d, 1H),8.45-8.55 (m, 1H), 8.40-8.45 (m, 2H), 8.07-8.12 (m, 1H), 8.03-8.07 (m,1H), 7.5-7.6 (m, 3H), 7.38-7.44 (m, 2H), 7.29 (d, 1H); MS (ESI⁺) m/z 326(M+1); H-PGDS FPBA IC₅₀: 0.15 μM; H-PGDS inhibitor EIA IC₅₀: 0.023 μM.

Example 16 Preparation of2-phenyl-5-(2-(2-(pyridin-3-yl)ethyl)-1H-imidazol-5-yl)pyrimidine

The title compound was prepared by subjecting(E)-2-phenyl-5-(2-(2-(pyridin-3-yl)vinyl)-1H-imidazol-5-yl)pyrimidine(Example 15, 7 mg, 0.02 mmol) to hydrogenation using 10% palladium oncarbon (dry, 1 mg) in ethanol (3 mL). After five days, the reactionmixture was filtered through Celite using ethanol to rinse. Evaporationprovided the title compound as a brown solid (7 mg, quantitative yield);melting point 113° C.; ¹H-NMR (400 MHz; CD₃OD) δ 9.16 (s, 2H), 8.39-8.44(m, 4H), 7.64 (s, 1H), 7.52-7.53 (m, 5H)), 3.12-3.19 (m, 4H); LC/MS(ESI⁺) m/z 328; H-PGDS FPBA IC₅₀: 0.3 μM.

Piperidine-, pyrrolidine-, and azetidine-containing compounds of theexemplary embodiments (20a-c) may be prepared according to the generalsynthetic route illustrated in Scheme 3, wherein R² is a carbon-boundpiperidinyl, pyrrolidinyl, or azetidinyl group as shown in Scheme 5. Anα-bromoketone intermediate 12 is reacted with a regioisomer ofN-Boc-piperidine-carboxylic acid 17a, N-Boc-pyrrolidine-carboxylic acid17b, or with N-Boc-azetidin-3-carboxylic acid 17c in the presence of abase, such as cesium carbonate, in a solvent, such as DMF to provide thecorresponding ester-ketone intermediates 18a-c. Each intermediate 18a-cmay be converted to its corresponding imidazole 19a-c in the presence ofammonium acetate in a solvent, such as toluene, with heating. Removal ofthe Boc group takes place in the presence of trifluoroacetic acid toafford amine compounds of general structure 20a-c. Examples 17-19,21-22, 28, and 30 may be prepared according to this general route.

Example 17 Preparation of tert-butyl4-(5-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate

To a solution consisting of1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (170 mg, 0.74 mmol)in dimethylformamide (7 mL) was added cesium carbonate (459 mg, 1.44mmol) and the reaction mixture was stirred for 15 minutes. To thereaction mixture was added 2-bromo-1-(2-phenylpyrimidin-5-yl)ethanone(Example 14, Step B, 200 mg, 0.72 mmol) and the mixture was stirred fortwo hours. Water was added to the reaction mixture and the organicmaterial was extracted with ethyl acetate. The organic phase was driedover magnesium sulfate, filtered, and concentrated under reducedpressure to provide a yellow semi-solid (240 mg). The solid wasdissolved in toluene, anhydrous ammonium acetate (1.1 g, 14 mmol) wasadded and the reaction mixture was heated at 112° C. for four hours. Thereaction mixture was cooled to room temperature, diluted with water andthe organic material was extracted two times with ethyl acetate. Thecombined organic phase was washed with 1:9 v/v brine-water, then brine,and dried over magnesium sulfate, filter, and concentrated under reducedpressure. The residue was chromatographed on silica (25 g) eluted with1:1 v/v to 4:1 ethyl acetate-hexane to afford the title compound (139mg) as a yellow solid; R_(f) 0.49 with 1:4 v/v hexanes-ethyl acetate;¹H-NMR (400 MHz; DMSO-d₆) δ 9.2 (s, 2H), 8.35-8.45 (m, 2H), 7.8 (5, 1H),7.4-7.6 (m, 3H), 3.9-4.1 (m, 2H), 2.8-3.0 (m, 3H), 2.8-2.95 (m, 2H),1.5-1.7 (M, 2H), 1.4 (m, 9H); MS (ESI⁺) m/z 406 (M+1); H-PGDS FPBA IC₅₀:0.15 μM.

Example 18 Preparation of2-phenyl-5-(2-(piperidin-4-yl)-1H-imidazol-5-yl)pyrimidine

Solid tert-butyl4-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate(Example 17, 122 mg, 0.30 mmol) was treated with trifluoroacetic acid2.0 mL) at room temperature for 15 minutes. Three times the reactionmixture was diluted with toluene and concentrated under reduced pressureto provide a dark semi-solid. The crude material was chromatographed onsilica (12 g) eluted with 1:5:85 v/v aceticacid-methanol-dichloromethane. Some clean fractions were collected,concentrated, and the purified material was three times diluted withtoluene and concentrated then promoted to solidify under hexane withscratching to afford the title compound (19 mg) as a light-pink acetatesalt. The remaining fractions were collected, concentrated, three timesdiluted with toluene and concentrated to afford a semi-solid; R_(f) 0.17with Jan. 10, 1990 v/v acetic acid/methanol/dichloromethane; ¹H-NMR (400MHz; DMSO-d₆) δ 9.20 (s, 2H), 8.6-8.8 (br d, 1H), 8.3-8.5 (m, 3H), 7.83(s, 1H), 7.45-7.55 (m, 3H), 3.2-3.5 (m, 2H), 2.95-3.2 (m, 3H), 2.1-2.2(m, 2H), 1.8-2.0 (m, 5H); MS (ESI⁺) m/z 306 (M+1); H-PGDS FPBA IC₅₀: 1μM.

Example 19 Preparation of5-(2-(1-benzylpiperidin-4-yl)-1H-imidazol-5-yl)-2-phenylpyrimidine

Step A: Preparation of sodium 1-benzylpiperidine-4-carboxylate

To a solution consisting of ethyl 1-benzylpiperidine-4-carboxylate (500mg, 2.02 mmol) in ethanol (10 mL) was added 1 N sodium hydroxide (2.02mL, 2.02 mmol) and the reaction mixture was stirred at room temperatureovernight. Most of the ethanol was removed under reduced pressure andstirring was continued for six hours. Toluene was added to remove mostof the water by azeotrope and the material was dried under high vacuumovernight to provide the title intermediate as a white solid.

Step B: Preparation of5-(2-(1-benzylpiperidin-4-yl)-1H-imidazol-4-yl)-2-phenylpyrimidine

To a solution consisting of 2-bromo-1-(2-phenylpyrimidin-5-yl)ethanone(Example 14, Step B, 50 mg, 0.18 mmol) in tetrahydrofuran (1.5 mL) atroom temperature was added sodium 1-benzylpiperidine-4-carboxylate (StepA, 48 mg, 0.20 mmol). The reaction mixture was warmed to 40° C. for onehour, and more sodium 1-benzylpiperidine-4-carboxylate (67 mg, 0.29mmol) was added and warmed at 40° C. for two hours. The reaction mixturewas cooled to room temperature, stirred vigorously while water (15 mL)was added quickly. The precipitate was filtered, washed with water anddried under high vacuum overnight to provide crude material (43.3 mg)that was dissolved in toluene (4 mL). To this solution was added freshlyprepared ammonium acetate under toluene (400 mg wet with toluene andacetic acid). The reaction mixture was heated at 112° C. for 3.5 hours,cooled to room temperature, separated from the solidified ammoniumacetate, concentrated under reduced pressure and chromatographed onsilica (4 g) eluted with ethyl acetate and 1:9 v/v ethanol-ethylacetate. The product was triturated under ethylacetate/hexane/dichloromethane (0.3 mL) and filtered to the titlecompound (10 mg) as a tan crystalline-like solid; R_(f) 0.17 with 1:9v/v ethanol-ethyl acetate; melting point 223° C.; ¹H-NMR (400 MHz;DMSO-d₆) δ 9.20 (s, 2H), 8.35-8.45 (m, 2H), 7.80-7.82 (m, 1H), 7.5-7.6(m, 4H), 7.3-7.4 (m, 4H), 7.2-7.3 (m, 1H), 3.5 (s, 2H), 2.7-2.9 (m, 2H),2.65-2.8 (m, 1H), 2.0-2.2 (m, 2H), 1.85-1.95 (m, 2H), 1.7-1.85 (m, 2H);MS (ESI⁺) m/z 396 (M+1); H-PGDS FPBA IC₅₀: 0.08 μM; H-PGDS inhibitor EIAIC₅₀: 0.006 μM.

The compounds of general structure 20a-c shown in Scheme 5 may befurther derivatized to compounds of general structure 21a-c asillustrated in Scheme 6. A compound 20a, 20b, or 20c may be alkylated,acylated, or arylated by a number of methods known to those ordinarilyskilled in the art to provide compounds 21a, 21b, and 21c, respectively,of the exemplary embodiments. In general, an amine intermediate 20a-c isreacted with an electrophile Q-(CH₂)_(q)-LG, wherein Q and q are asdefined above and LG is a leaving group, such as chloro, bromo, iodo,O-tosyl, O-methanesulfonyl, or O-trifluoromethanesulfonyl in thepresence of a base, such as triethylamine, cesium carbonate, or sodiumtert-butoxide, in a solvent such as THF, DMF, dichloromethane, ortoluene. Groups with the general structure Q-(CH₂)_(q)— may further bederivatized or manipulated in order to convert the compound to anothercompound of the exemplary embodiment. Such conversions include, but arenot limited to, oxidation, reduction, deprotection, homologation,alkylation, acylation, or arylation and may be carried out by methodsknown to those ordinarily skilled in the art. The preparations ofExamples 20, 23, 24, 25B, 26, 27, 29, and 31 employ this general method.

Example 20 Preparation of(4-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)(pyridin-3-yl)methanone

To a 0° C. solution of2-phenyl-5-(2-(piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine (76 mg, 0.25mmol) in tetrahydrofuran (4 mL) was added triethylamine (51 mg, 0.50mmol) followed by nicotinoyl chloride (49 mg, 0.27 mmol) and thereaction mixture was stirred for 1 hour at 0° C. then allowed to warm toroom temperature. The reaction was diluted with water and the organicmaterial extracted three times with ethyl acetate. The combined organicphase was dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The crude solid was chromatographed on silica (4 g)and eluted with ethanol-ethyl acetate to give the title compound as asolid; melting point 234° C.; R_(f) 0.31 with 0.5/10/40/50 aceticacid-isopropanol-hexane-dichloromethane; MS (ESI⁺) m/z 411 (M+1); H-PGDSFPBA IC₅₀: 0.45 μM.

Example 21 Preparation of (±)-tert-butyl3-(5-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate

To a solution consisting of(±)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (42 mg, 0.18mmol) in N,N-dimethylformamide (1.5 mL) was added cesium carbonate (117mg, 0.36 mmol) and the reaction mixture was stirred for 15 minutes. Tothe reaction mixture was added2-bromo-1-(2-phenylpyrimidin-5-yl)ethanone (Example 14, Step B, 50 mg,0.18 mmol) and the mixture was stirred for 1.5 hours. Water was added tothe vigorously stirred reaction mixture and the precipitate wasfiltered, washed with water and dried under high vacuum to provide alight green solid (42 mg). The solid (26 mg, 0.06 mmol) was dissolved intoluene, anhydrous ammonium acetate (146 mg, 1.9 mmol) was added and thereaction mixture was heated at 112° C. for four hours. The reactionmixture was cooled to room temperature and the liquid was separated fromthe solid and concentrated. The residue was chromatographed on silica (4g) eluted with 1:4:5 v/v dichloromethane-ethyl acetate-hexane.Crystallization from methanol and water afforded the title compound (6.5mg) as brown solid; R_(f) 0.29 with 1:1 v/v hexanes-ethyl acetate;melting point 130° C.; ¹H-NMR (400 MHz; DMSO-d₆) δ 9.20 (s, 2H),8.35-8.45 (m, 2H), 7.85 (d, 1H), 7.5-7.6 (m, 3H), 4.0-4.4 (br d, 1H),3.85-4.0 (m, 1H), 2.9-3.2 (br s, 1H), 2.7-2.9 (m, 2H), 2.0-2.2 (m, 1H),1.65-1.75 (m, 2H), 1.3-1.5 (m, 1H), 1.41 (s, 9H); MS (ESI⁺) m/z 406(M+1); H-PGDS FPBA IC₅₀: 0.2 μM.

Example 22 Preparation of(±)-2-phenyl-5-(2-(piperidin-3-yl)-1H-imidazol-5-ylpyrimidine

Solid (±)-tert-butyl3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate(Example 21) was treated with 0.5 mL of trifluoroacetic acid at roomtemperature for 0.5 hour. Three times the reaction mixture was dilutedwith toluene and concentrated to give a dark semi-solid. The crudematerial was chromatographed on silica (4 g) eluted with 1:10:90 v/vacetic acid-methanol-dichloromethane. The clean fractions werecollected, concentrated under reduced pressure, and the material wasthree times diluted with toluene and concentrated, then dried under highvacuum to afford the title compound as a pale yellow solid; R_(f) 0.17with 1:10:90 v/v acetic acid-methanol-dichloromethane; melting point140° C.; ¹H-NMR (400 MHz; DMSO-d₆) δ 9.22 (s, 2H), 8.5-9.2 (br s, 2H),8.35-8.45 (m, 2H), 7.9 (d, 1H), 7.4-7.5 (m, 3H), 3.4-3.6 (m, 2H),3.2-3.4 (m, 2H), 2.9-3.1 (m, 1H), 2.0-2.2 (m, 1H), 1.6-1.9 (m, 3H); MS(ESI⁺) m/z 306 (M+1); H-PGDS FPBA IC₅₀: 1.25 μM.

Example 23 Preparation of(±)-5-(2-(1-benzylpiperidin-3-yl)-1H-imidazol-5-yl)-2-phenylpyrimidine

To a solution consisting of(±)-2-phenyl-5-(2-(piperidin-3-yl)-1H-imidazol-4-yl)pyrimidine (Example22, 40 mg, 0.13 mmol) in dimethylformamide (2 mL) was added cesiumcarbonate (85 mg, 0.26 mmol) followed by benzyl bromide (27 mg, 0.16mmol). The reaction mixture was stirred at room temperature for one hourand diluted with water and the organic material was extracted twice withethyl acetate. The combined organic phase was dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. The residuewas dissolved in dichloromethane/ethyl acetate and chromatographed onsilica (4 g) eluted with 1:9 v/v ethanol-ethyl acetate. The purifiedmaterial was diluted with toluene and concentrated. Solidification ofthe product was promoted with scratching under dichloromethane andhexane to afford the title compound (20 mg) as a colorless solid;melting point 179° C.; R_(f) 0.19 with 1:9 v/v ethanol-ethyl acetate;¹H-NMR (400 MHz; DMSO-d₆) δ 12.1 (s, 1H), 9.18 (s, 2H), 8.2-8.4 (m, 2H),7.8 (s, 1H), 7.4-7.6 (m, 4H), 7.22-7.35 (m, 4H), 7.18-7.22 (m, 4H),3.4-3.6 (m, 2H), 2.9-3.0 (m, 2H), 2.7-2.9 (m, 1H), 2.02-2.1 (M, 1H),1.9-2.1 (m, 2H), 1.62-1.8 (m, 1H), 1.5-1.62 (m, 2H); MS (ESI⁺) m/z 396(M+1); H-PGDS FPBA IC₅₀: 0.6 μM.

Example 24 Preparation of2,2,2-trifluoro-1-(3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)ethanol

To a room temperature solution of(±)-2,2,2-trifluoro-1-(3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-ylethanone(18 mg, 0.04 mmol) in tetrahydrofuran (1 mL) was addedborane-tetrahydrofuran (1 M, 0.13 mL, 0.13 mmol). The reaction mixturewas heated at 65° C. for four hours, cooled, treated carefully with 6 mLof 6N HCl and 2 mL of ethanol and heated at 65° C. for one hour. Thecooled reaction mixture was extracted four times with ethyl acetate andthe organic phase was dried over magnesium sulfate, filtered, androtovapped. The residue was chromatographed on silica (4 g) and elutedwith 1:20:80 to 5:30:70 triethylamine-isopropanol-hexanes to give thetitle compound as a bright yellow solid. white solid; R_(f) 0.15 with1:20:80 v/v triethylamine-isopropanol-hexanes; MS (ESI⁺) m/z 404 (M+1);H-PGDS FPBA IC₅₀: 10 μM.

Examples 25A and 25B Preparation of(±)—N-methyl-3-(1-(methylcarbamoyl)-4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide(Example 25A) and(±)—N-methyl-3-(5-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide (Example 25B)

To a suspension consisting of2-phenyl-5-(2-(piperidin-3-yl)-1H-imidazol-4-yl)pyrimidine (Example 22,40 mg, 0.13 mmol) in dichloromethane (2 mL) was added methyl isocyanate(9 mg, 0.16 mmol) and the reaction mixture was stirred for one hour. TLC(1:10:90 v/v acetic acid-methanol-dichloromethane) indicated noreaction. The mixture was diluted with tetrahydrofuran (2 mL) to providea homogeneous solution, and methyl isocyanate (9 mg, 0.16 mmol) wasadded. The reaction mixture was stirred overnight and the precipitatewas filtered to provide(±)—N-methyl-3-(1-(methylcarbamoyl)-4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide(Example 25A, 10 mg) as a white solid; R_(f) 0.31 with 1:9 v/vethanol-ethyl acetate; ¹H-NMR (400 MHz; DMSO-d₆) δ 9.20 (s, 2H), 8.59(br qt, 1H), 8.35-8.45 (m, 2H), 8.18 (s, 1H), 7.45-7.55 (m, 3H), 6.40(br qt, 1H), 4.1-4.2 (m, 1H), 3.9-4.0 (m, 1H), 3.2-3.4 (m, 1H), 2.9-3.1(m, 1H), 2.81 (d, 3H), 2.65-2.75 (m, 1H), 2.55 (d, 3H), 2.0-2.1 (m, 1H),1.6-1.7 (m, 2H), 1.3-1.45 (m, 1H); MS (ESI⁺) m/z 420 (M+1); H-PGDS FPBAIC₅₀: 0.62 μM.

The filtrate was diluted with water. The organic material was extractedtwice with ethyl acetate and the combined organic phase was washed withbrine, dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The crude material was purified on a silica column toafford(±)—N-methyl-3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxamide(Example 25B, 5.5 mg) as a solid; R_(f) 0.17 with 1:9 v/v ethanol-ethylacetate; ¹H-NMR (400 MHz; DMSO-d₆) δ12.2 (s, 1H), 9.21 (s, 2H),8.35-8.45 (m, 2H), 7.84-7.85 (m, 1H), 7.50-7.55 (m, 3H), 6.45 (br qt,1H), 4.15-4.22 (m, 1H), 3.85-3.95 (m, 1H), 2.85-2.95 (m, 1H), 2.65-2.85(m, 2H), 2.55 (d, 3H), 2.51 (d, 3H), 2.0-2.1 (m, 1H), 1.6-1.8 (m, 2H),1.35-1.5 (m, 1H); MS (ESI⁺) m/z 363 (M+1); H-PGDS FPBA IC₅₀: 0.3 μM.

Example 26 Preparation of(±)-cyclopropyl(3-(5-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)methanone

The title compound is prepared in the same manner as Example 27 exceptthat cyclopropanecarbonyl chloride is used instead of trifluoroaceticanhydride. The reaction is carried out at 0° C. and allowed to warm toroom temperature. The reaction mixture is diluted with water, extractedwith ethyl acetate and the organic phase is dried over magnesiumsulfate, filtered, and evaporated. The crude is purified on a silicacolumn.

Example 27 Preparation of(±)-2,2,2-trifluoro-1-(3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)ethanone

To a 0° C. solution of2-phenyl-5-(2-(piperidin-3-yl)-1H-imidazol-4-yl)pyrimidine (40 mg, 0.13mmol) in tetrahydrofuran (2 mL) was added triethylamine (26 mg, 0.26mmol) followed by trifluoroacetic anhydride (30 mg, 0.14 mmol) and thereaction mixture was stirred for 1 hour at 0° C. then allowed to warm toroom temperature. To −78° C. solution of2-phenyl-5-(2-(piperidin-3-yl)-1H-imidazol-4-yl)pyrimidine (40 mg, 0.13mmol) in tetrahydrofuran (2 mL) was added triethylamine (26 mg, 0.26mmol) followed by trifluoroacetic anhydride (30 mg, 0.14 mmol) and thereaction mixture was stirred and allowed to slowly warm to roomtemperature. The two reaction mixtures were combined, the volatilematerials were removed, and the crude reaction mixture was treated with0.5 mL of N-methylpiperazine at 50° C. for 1 hour. The addition of 30 mLof water caused a precipitate that was filtered and washed with waterand dried in high vacuum. The crude solid was chromatographed on 4 g ofsilica eluted with ethyl acetate/hexane to give 30 mg of the titlecompound as a white solid. R_(f) 0.20 with 1:1 v/v hexanes-ethylacetate; ¹H-NMR (400 MHz; DMSO-d₆) δ 9.21 (s, 2H), 8.35-8.45 (m, 2H),7.85-7.90 (m, 1H), 7.5-7.6 (m, 3H), 4.20-4.55 (m, 1H), 3.80-4.15 (m,1H), 2.0-3.7 (m, 3H), 2.1-2.2 (m, 1H), 1.75-2.0 (m, 2H), 1.5-1.7 (m,1H); MS (ESI⁺) m/z 402 (M+1); H-PGDS FPBA IC₅₀: 0.09 μM.

Additional elution of the column with 1/9 ethanol/ethyl acetate provided6 mg of a white solid identified as1-(3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)ethanone.R_(f) 0.17 with 1:9 v/v ethanol-ethyl acetate; MS (ESI⁺) m/z 348 (M+1);H-PGDS FPBA IC₅₀: 0.09 μM.

Example 28 Preparation of (±)-tert-butyl3-(5-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution consisting of1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (159 mg, 0.74 mmol)in dimethylformamide (7 mL) was added cesium carbonate (459 mg, 1.44mmol) and the reaction mixture was stirred for 15 minutes. To thereaction mixture was added 2-bromo-1-(2-phenylpyrimidin-5-yl)ethanone(Example 14, Step B, 200 mg, 0.72 mmol) and the mixture was stirred fortwo hours. Water was added to the reaction mixture and the organicmaterial was extracted with ethyl acetate. The organic phase was driedover magnesium sulfate, filtered, and concentrated to afford a yellowsemi-solid (250 mg). The solid was dissolved in toluene, anhydrousammonium acetate (1.2 g, 15 mmol) was added and the reaction mixture washeated at 112° C. for four hours. The reaction mixture was cooled toroom temperature, diluted with water and the organic material wasextracted twice with ethyl acetate. The combined organic phase waswashed with 1:9 v/v brine-water, then brine, and dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. The residuewas chromatographed on silica (25 g). Elution with 1:1 v/v to 4:1 ethylacetate-hexane afforded the title compound (83 mg) as a yellow solid;R_(f) 0.43 with 1:4 v/v hexanes-ethyl acetate; melting point 219° C.;¹H-NMR (400 MHz; DMSO-d₆) δ 9.18 (s, 2H), 8.3-8.4 (m, 2H), 7.24 (d, 1H),7.45-7.55 (m, 3H), 3.6-3.7 (m, 1H), 3.4-3.6 (m, 3H), 3.2-3.4 (m, 3H,under water peak), 2.0-2.35 (m, 2H), 1.4 (m, 9H); MS (ESI⁺) m/z 392(M+1); H-PGDS FPBA IC₅₀: 0.15 μM.

Example 29 Preparation of(±)-5-(2-(1-benzylpyrrolidin-3-yl)-1H-imidazol-5-yl)-2-phenylpyrimidine

The title compound is prepared in the same manner as example 23 exceptthat (±)-2-phenyl-5-(2-(pyrrolidin-3-yl)-1H-imidazol-5-yl)pyrimidine isused instead of(±)-2-phenyl-5-(2-(piperidin-3-yl)-1H-imidazol-4-yl)pyrimidine.

Example 30 Preparation of(±)-2-phenyl-5-(2-(pyrrolidin-3-yl)-1H-imidazol-5-yl)pyrimidine

The title compound was prepared according to the method described inExample 22, except that (±)-tert-butyl3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(Example 28) was used instead of (±)-tert-butyl3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate.MS (ESI⁺) m/z 292 (M+1); H-PGDS FPBA IC₅₀: 2 μM.

Example 31 Preparation of(±)—N-methyl-3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxamide

The title compound is prepared in the same manner as Example 25B exceptthat (±)-2-phenyl-5-(2-(pyrrolidin-3-yl)-1H-imidazol-5-yl)pyrimidine isused instead of(±)-2-phenyl-5-(2-(piperidin-3-yl)-1H-imidazol-4-yl)pyrimidine and thereaction is done in tetrahydrofuran instead of a combination ofdichloromethane and tetrahydrofuran.

H-PGDS H-PGDS FPBA Inhibitor EIA Ex. R⁷ IC₅₀ (μM) IC₅₀ (μM) 5 H 5 32 Me7.6 33 Bn 2

Example 32 Preparation of5-(1-methyl-1H-imidazol-5-yl)-2-phenylpyrimidine

The title compound was prepared by the method described in Example 1,Steps A-C, except that commercially available 1-methylimidazole(Aldrich) was used instead of 2-phenylimidazole in Step B; R_(f) 0.31with 95:5 v/v dichloromethane-methanol; ¹H-NMR (400 MHz; CDCl₃) δ 8.87(s, 2H), 8.48 (m, 2H), 7.63 (s, 1H), 7.54 (m, 3H), 7.28 (s, 1H); MS(ESI⁺) m/z 237.1 (M+1); melting point 144° C.; H-PGDS FPBA IC₅₀: 7.6 μM.

Example 33 Preparation of5-(1-benzyl-1H-imidazol-5-yl)-2-phenylpyrimidine

The title compound was prepared by the method described in Example 1,Steps A-C, except that imidazole was used instead of 2-phenylimidazolein Step B; R_(f) 0.18 with 100% ethyl acetate; melting point 140° C.;¹H-NMR (400 MHz; DMSO-d₆) δ 8.85 (s, 2H), 8.39 (m, 2H), 8.05 (s, 1H),7.55 (m, 3H), 7.45-7.20 (m, 5H) 6.98 (dd, 2H), 5.43 (s, 2H); MS (ESI⁺)m/z 313.0 (M+1); H-PGDS FPBA IC₅₀: 2 μM.

H-PGDS H-PGDS FPBA Inhibitor EIA Ex. Z¹—(CH₂)_(n) IC₅₀ (μM) IC₅₀ (μM)  5 H (Z¹ = H, n = 0) 5 34 Bn (Z¹ = Ph, n = 1) 4 35 Me (Z¹ = H, n = 1) 36(3-pyridyl)-CH₂— 37

Example 34 Preparation of5-(1-benzyl-1H-imidazol-4-yl)-2-phenylpyrimidine

Step A: Preparation of 2-phenyl-5-(1-trityl-1H-imidazol-4-yl)pyrimidine

To a solution of 4-Iodo-1-trityl-1H-imidazole (Synthonix, 2.0 g, 4.58mmol) in THF (50 mL) at room temperature was added ethylmagnesiumbromide (Aldrich, 1.0 M solution in THF, 5.5 mL, 5.50 mmol) under dryconditions. After stirring for 90 minutes, zinc chloride (Aldrich,0.749. g, 5.50 mmol) was added to the reaction mixture. After stirringfor an additional 90 minutes, tetrakis(triphenyl)phosphine)palladium(Strem, 0.529 g, 0.46 mmol) and 5-bromo-2-phenylpyrimidine (as preparedin Example 1, step A, 1.29 g, 5.50 mmol) were added to the reactionmixture. The reaction mixture was heated in a 70° C. oil bath overnight.Upon cooling, the reaction was diluted with dichloromethane and washedwith 0.5 M EDTA buffer (at pH ˜9) (2×250 mL) followed by brine (150 mL).The organics were dried over sodium sulfate, filtered, and concentrated.The crude product was purified by flash silica column chromatographyusing an 80 g Silicycle® column (elution with 10-30% ethyl acetate inhexane) which afforded the desired intermediate,2-phenyl-5-(1-trityl-1H-imidazol-4-yl)pyrimidine, as a white solid (1.38g, 65%). R_(f) 0.87 with 95:5 v/v dichloromethane-methanol; ¹H-NMR (400MHz; DMSO-d₆) δ 9.29 (s, 2H), 8.42 (m, 2H), 7.92 (d, 1H), 7.62 (d, 1H),7.56-7.43 (m, 13H), 7.24-7.22 (m, 6H); MS (ESI⁻) m/z 463.0 (M−1); H-PGDSFPBA IC₅₀: >20 μM.

Step B: Preparation of 5-(1H-imidazol-4-yl)-2-phenylpyrimidine

The title intermediate is chemically equivalent to Example5,5-(1H-imidazol-5-yl)-2-phenylpyrimidine. An alternative preparation ofthis compound is presented in this step. To a solution consisting of2-phenyl-5-(1-trityl-1H-imidazol-4-yl)pyrimidine (Step A, 0.786 g, 1.69mmol) in ethanol (50 mL) was added concentrated aqueous hydrochloricacid (5 mL) at room temperature. The reaction mixture was heated in a50° C. oil bath for 90 minutes. Upon cooling, the reaction wasconcentrated under vacuum to about half the original amount of solvent.Ethyl ether (30 mL) was added to the mixture and the product precipitatewas collected by filtration. The solid was washed with excess ethylether and then dried under vacuum to afford the intermediate,5-(1H-imidazol-4-yl)-2-phenylpyrimidine, as a white solid (0.336 g,76%). R_(f) 0.14 with 95:5 v/v dichloromethane-methanol; ¹H-NMR (400MHz; DMSO-d₆) δ9.49 (s, 2H), 9.41 (d, 1H), 8.49-8.44 (m, 3H), 7.61-7.58(m, 3H); MS (ESI⁺) m/z 223.1 (M+1); H-PGDS FPBA IC₅₀: 5 μM.

Step C: Preparation of 5-(1-benzyl-1H-imidazol-4-yl)-2-phenylpyrimidine

To a solution consisting of 5-(1H-imidazol-4-yl)-2-phenylpyrimidine(Step B, 0.050 g, 0.193 mmol) in N,N-dimethylformamide (10 mL) was addedpotassium carbonate (0.133 g, 0.965 mmol) at room temperature under dryconditions. After heating the reaction mixture in an 80° C. oil bath forone hour, benzyl bromide (Aldrich, 0.039 g, 0.231 mmol) was added to themixture. The solution was left stirring in an 80° C. oil bath for 24hours. Upon cooling, the reaction was diluted with dichloromethane (100mL) and washed with saturated aqueous ammonium chloride (50 mL), water(50 mL) and brine (50 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated. The residue was chromatographed onsilica. Elution through an 8-g Silicycle® flash silica cartridge withgradient of 100% dichloromethane to 5% methanol in dichloromethaneafforded the title compound as a white solid (22 mg, 36%). R_(f) 0.56with 95:5 v/v dichloromethane-methanol; melting point 195° C.; ¹H-NMR(400 MHz; DMSO-d₆) δ 9.25 (s, 2H), 8.44-8.42 (m, 2H), 8.03 (s, 2H),7.56-7.54 (m, 3H), 7.45-7.36 (m, 5H), 5.38 (s, 2H); MS (ESI⁺) m/z 313.1(M+1); H-PGDS FPBA IC₅₀: 4 μM.

Example 35 Preparation of5-(1-methyl-1H-imidazol-4-yl)-2-phenylpyrimidine

The title compound is prepared by the method described in Example 34,Steps A-C, except that iodomethane is used instead of benzyl bromide inStep C.

Example 36 Preparation of5-(1-benzyl-1H-imidazol-4-yl)-2-phenylpyrimidine

The title compound is prepared by the method described in Example 34,Steps A-C, except that 3-bromomethypyridine hydrobromide is used insteadof benzyl bromide in Step C.

Example 37 Preparation of2-phenyl-5-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine

The title compound was prepared by the method described in Example 34,Steps A-C, except that tert-butyl 4-(tosyloxy)piperidine-1-carboxylateis used instead of benzyl bromide in Step C. The nitrogen of thepiperidine is deprotected and derivatized in the manner described inExamples 22 and 24, respectively.

H-PGDS H-PGDS FPBA Inhibitor EIA Ex. R² IC₅₀ (μM) IC₅₀ (μM) 38 Ph 4 39Bn 10 40 3-pyridyl 0.625 0.37

Example 38 Preparation of2-phenoxy-5-(2-phenyl-1H-imidazol-5-yl)pyrimidine

Step A: Preparation of 5-bromo-2-phenoxypyrimidine

A mixture consisting of 5-bromo-2-iodopyrimidine (Bridge Organics, 1.01g, 3.57 mmol), phenol (Aldrich, 3.35 g, 35.7 mmol), and potassiumcarbonate (Aldrich, 4.93 g, 35.7 mmol) was stirred neat at 165° C. undera nitrogen atmosphere for four hours. After cooling to room temperature,the mixture was partitioned between ethyl acetate (250 mL) and 1 Nhydrochloric acid (4×200 mL). The organic layer was washed with 1 Nhydrochloric acid until disappearance of color in the aqueous layer. Thephases were separated and the organic phase was washed with water (100mL) and brine (100 mL). The organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to provide anorange oil (1.1 g). The product was purified by flash silica columnchromatography. Elution through an 80-g Silicycle® flash silicacartridge with 10% ethyl acetate in hexanes afforded the title compoundas a white solid (0.82 g, 92% yield); R_(f) 0.51 with 8:2 v/vhexanes-ethyl acetate; ¹H-NMR (400 MHz; CDCl₃) δ 8.56 (s, 2H), 7.46-7.41(m, 2H), 7.30-7.24 (m, 1H), 7.20-7.16 (m, 2H); MS (APCI⁺) m/z 252.9(M+1).

Step B: Preparation of 1-(2-phenoxypyrimidin-5-yl)ethanone

The title intermediate was prepared by the method described in Example14, Step B, except that 5-bromo-2-phenoxypyrimidine was used instead of5-bromo-2-phenylpyrimidine. The residue from the work up was dissolvedin dichloromethane and diluted with hexane, was applied to an 80-gsilica column eluted with 1:4 ethyl acetate-hexane to afford the titleintermediate (690 mg, 65% yield); R_(f) 0.29 with 3:1 v/v hexanes-ethylacetate solvent system; ¹H-NMR (400 MHz; DMSO-d₆) δ 9.17 (s, 2H),7.4-7.6 (m, 2H), 7.2-7.4 (m, 3H), 2.60 (s, 3H); MS (ESI⁺) m/z 215 (M+1).

Step C: Preparation of 2-bromo-1-(2-phenoxypyrimidin-5-yl)ethanone

To a solution consisting of 1-(2-phenoxypyrimidin-5-yl)ethanone (Step B,400 mg, 1.87 mmol) in dichloromethane (14 mL) was addedtetrabutylammonium tribromide (990 mg, 2.05 mmol). The reaction mixturewas sealed with a screw top and warmed at 40° C. overnight and allowedto cool to room temperature. Hexane (4 mL) was subsequently added. Afterthree hours and little precipitation, additional (150 mg)tetrabutylammonium tribromide was added and the reaction mixture wasstirred overnight at room temperature. The pale yellow precipitate thatformed was collected on a filter and washed with 1:1dichloromethane-hexane to afford the title intermediate (375 mg, 68%);R_(f) 0.43 with 3:1 v/v hexanes-ethyl acetate; MS (ESI⁺) m/z 295, 293(M+1, Br isotopes).

Step D: Preparation of 2-oxo-2-(2-phenoxypyrimidin-5-yl)ethyl benzoate

To a mixture consisting of benzoic acid (21 mg, 0.17 mmol) and cesiumcarbonate (112 mg, 0.34 mmol) in DMF (2.5 mL) was added2-bromo-1-(2-phenoxypyrimidin-5-yl)ethanone (50 mg, 0.17 mmol). Uponstirring at room temperature (30 minutes), the solution became darkamber. The reaction mixture was combined with ethyl acetate and washedsequentially with water and brine. The organic layer was dried withsodium sulfate, filtered and concentrated under reduced pressurefollowed by concentration with toluene. The title intermediate wasisolated as a dark yellow solid (40 mg, 70% yield); TLC (silica) R_(f)0.44, 3:1 v/v hexanes-ethyl acetate.

Step E: Preparation of 2-phenoxy-5-(2-phenyl-1H-imidazol-5-yl)pyrimidine

A mixture consisting of 2-oxo-2-(2-phenoxypyrimidin-5-yl)ethyl benzoate(Step A, 40 mg), freshly prepared ammonium acetate (315 mg wet withtoluene), and toluene (4 mL) was heated in a capped vial to 112° C.overnight. The reaction mixture was poured into a 0.1 M aqueous sodiumbicarbonate solution and extracted twice with ethyl acetate. The organiclayer was washed with brine, dried with magnesium sulfate, filtered andconcentrated under reduced pressure. The crude brown solid was purifiedby flash chromatography using a 4:1 to 1:1 hexanes-ethyl acetategradient affording the title compound (11.2 mg, 29% yield) as a lighttan solid; melting point 254° C.; ¹H-NMR (400 MHz; DMSO-d₆) δ 9.05 (s,2H), 7.96-8.02 (m, 2H), 7.85-7.92 (m, 2H), 7.42-7.54 (m, 4H), 7.35-7.41(m, 1H), 7.20-7.29 (m, 2H); LC/MS (ESI⁺) m/z 315; H-PGDS FPBA IC₅₀: 4μM.

Example 39 Preparation of5-(2-benzyl-1H-imidazol-4-yl)-2-phenoxypyrimidine

Step A: Preparation of 2-oxo-2-(2-phenoxypyrimidin-5-yl)ethyl2-phenylacetate

The title intermediate was prepared according to the method described inExample 38, Step D except that phenylacetic acid was used instead ofbenzoic acid. The title intermediate was isolated as a dark yellow solid(47 mg); TLC (silica) R_(f) 0.64, 3:1 v/v hexanes-ethyl acetate.

Step B: Preparation of 5-(2-benzyl-1H-imidazol-4-yl)-2-phenoxypyrimidine

The title compound was prepared according to the procedure described inExample 27, Step E except that 2-oxo-2-(2-phenoxypyrimidin-5-yl)ethyl2-phenylacetate was used instead of2-oxo-2-(2-phenoxypyrimidin-5-yl)ethyl benzoate. The crude brown solidwas purified by flash chromatography using a 4:1 to 1:1 hexanes-ethylacetate gradient affording the title compound (9.9 mg, 23% yield) as ayellow solid; melting point 60° C.; ¹H-NMR (400 MHz; DMSO-d₆) δ 8.97 (s,2H), 7.71 (s, 1H), 7.48-7.52 (m, 2H), 7.25-7.37 (m, 8H), 4.09 (s, 2H);LC/MS (ESI⁺) m/z 329; H-PGDS FPBA IC₅₀: 10 μM.

Example 40 Preparation of2-phenoxy-5-(2-(pyridin-3-yl)-1H-imidazol-4-yl)pyrimidine

Step A: Preparation of 2-oxo-2-(2-phenoxypyrimidin-5-yl)ethyl nicotinate

To a mixture consisting of nicotinic acid (23 mg, 0.19 mmol) and cesiumcarbonate (115 mg, 0.35 mmol) in tetrahydrofuran (1.5 mL) was added2-bromo-1-(2-phenoxypyrimidin-5-yl)ethanone (Example 38, Step C, 50 mg,0.17 mmol). The stirring mixture was heated to 40° C. for one hour,after which time some starting material had not completely dissolved andthe reaction was not completed as indicated by TLC.N,N-dimethylformamide (1.5 mL) was added and the reaction was stirred anadditional two hours at room temperature. The work up of Example 38,Step D was followed. The title intermediate was isolated as a darkyellow solid (31 mg, 54% yield); TLC (silica) R_(f) 0.17, 1:1hexanes-ethyl acetate.

Step B: Preparation of2-phenoxy-5-(2-(pyridin-3-yl)-1H-imidazol-4-yl)pyrimidine

The title compound was prepared according to the procedure in Example38, Step E, except that 2-oxo-2-(2-phenoxypyrimidin-5-yl)ethylnicotinate, prepared in Step A of this example, was used instead of2-oxo-2-(2-phenoxypyrimidin-5-yl)ethyl benzoate. The crude brown solidwas purified by flash chromatography using a 1:9 to 0:1 hexanes-ethylacetate gradient affording the title compound (7.1 mg, 24% yield) as atan solid; melting point 236° C.; ¹H-NMR (400 MHz; DMSO-d₆) δ 9.19 (s,1H), 9.05 (s, 2H), 8.58-8.59 (m, 1H), 8.30-8.33 (m, 1H), 7.99 (s, 1H),7.51-7.54 (m, 1H), 7.44-7.48 (m, 2H), 7.23-7.29 (m, 3H); LC/MS (ESI⁺)m/z 316; H-PGDS FPBA IC₅₀: 0.625 μM; H-PGDS inhibitor EIA IC₅₀: 0.37 μM.

H-PGDS H-PGDS FPBA Inhibitor EIA Ex. U¹ U² U³ U⁴ IC₅₀ (μM) IC₅₀ (μM)   5NH CH N CH 5 41 NH N CH CH 2.4 42 O CH CH N 7.8 43 NH N N N 2.5

Example 41 Preparation of 2-phenyl-5-(1H-pyrazol-3-yl)pyrimidinehydrochloride

Step A: Preparation of2-phenyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-Pyrazol-5-yl)pyrimidine

Diisopropyl 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-ylboronate (595mg, 1.46 mmol) prepared according to the procedure described in theJournal of Organic Chemistry, 2008, 73, 1241-1243) was combined withPd₂(dba)₃ (13 mg, 0.013 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19 mg, 0.033 mmol).1,4-Dioxane (10 mL) and 5-bromo-2-phenylpyrimidine (343 mg, 1.46 mmol)were added followed by 1.27 M aqueous K₃PO₄ (958 mg dissolved in 3.5 mLof water) and the mixture heated at 100° C. for 18 hours with stirring.The mixture was cooled to room temperature and filtered through Celitewashing with ethyl acetate. The solvent was removed under reducedpressure and the concentrate partitioned between water and ethylacetate. The organic phase was retained and dried with anhydrous sodiumsulfate. The solution was filtered and the solvent removed under reducedpressure. Purification by silica gel flash chromatography (9:1 to 3:2v/v hexane-ethyl acetate gradient) through a 12-g Silicycle® flashsilica cartridge gave title intermediate as a white solid (51 mg, 11%yield); R_(f) 0.70 with 40% ethyl acetate in hexane; MS (ESI⁺) m/z 307(M+1).

Step B: Preparation of 2-phenyl-5-(1H-pyrazol-3-yl)pyrimidinehydrochloride

2-Phenyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrimidine(Step A, 51 mg) was added to a 1 N hydrochloric acid solution inmethanol (5 mL). The solution was stirred at room temperature for twohours. MTBE (40 mL) was added to precipitate a white solid which wasfiltered and rinsed with MTBE and dried under high vacuum. The titlecompound was obtained as a white powder (11.4 mg, 27% yield); meltingpoint 264-273° C.; ¹H-NMR (300 MHz; CD₃OD) δ 10.0 (s, 1H), 9.29 (s, 2H),8.44 (dd, 2H), 7.86 (d, 1H), 7.54 (m, 3H), 6.95 (d, 1H); MS (ESI⁺) m/z223 (M+1); H-PGDS FPBA IC₅₀: 2.4 μM.

Example 42 Preparation of 2-(2-phenylpyrimidin-5-yl)oxazole

Oxazole (124 mg, 1.8 mmol) was dissolved in stirring tetrahydrofuran (20mL) under nitrogen at −78° C. and treated with n-butyllithium (2.0 M incyclohexane, 1.1 mL, 2.2 mmol) maintaining internal temperature below−60° C. After stirring ten minutes, ZnCl₂ (0.48 g, 3.5 mmol) was addedportionwise. The cooling bath was removed and the solution was allowedto reach room temperature.

Tetrakis(triphenylphosphine)palladium(0) (30 mg, 5 mole %) and5-bromo-2-phenylpyrimidine (309 mg, 1.30 mmol) were added and themixture heated at 60° C. for four hours. Solvent was removed underreduced pressure and the mixture partitioned between saturated aqueousammonium chloride and ethyl acetate. The organic phase was retained andadditional ethyl acetate extractions of the aqueous phase performed. Thecombined extracts were dried with anhydrous sodium sulfate, the solutionfiltered, and solvent removed under reduced pressure. Purification bysilica gel flash chromatography (9:1 to 7:3 v/v hexane-ethyl acetate)through a 12-g Silicycle® flash silica cartridge afforded the titlecompound as an off-white solid (17 mg, 6% yield); R_(f) 0.66 with 3:1v/v hexane-ethyl acetate; melting point 175-177° C.; ¹H-NMR (300 MHz;DMSO-d₆) δ 9.42 (s, 2H), 8.48 (dd, 2H), 8.41 (s, 1H), 7.56-7.62 (m, 3H),7.54 (s, 1H); MS (ESI⁺) m/z 224 (M+1), (ESI⁻) m/z 222 (M−1); H-PGDS FPBAIC₅₀: 7.8 μM.

Example 43 Preparation of 2-phenyl-5-(1H-tetrazol-5-yl)pyrimidine

A mixture consisting of 2-phenylpyrimidine-5-carbonitrile (200 mg, 1.10mmol), sodium azide (80 mg, 1.2 mmol) and ammonium chloride (66 mg, 1.2mmol) in DMF (3 mL) was stirred at 100° C. for 24 hours. The reactionmixture was allowed to cool to room temperature. Upon addition of 1Nhydrochloric acid (3 mL), a white solid precipitated. The precipitatewas isolated by filtration and recrystallized from ethanol to afford thetitle compound as a white solid (123 mg, 50% yield); melting point 237°C.; ¹H-NMR (400 MHz; DMSO-d₆) δ 9.51 (s, 2H), 8.51-8.53 (m, 2H),7.61-7.65 (m, 3H); LC/MS (ESI⁺) m/z 225; H-PGDS FPBA IC₅₀: 2.5 μM.

H-PGDS H-PGDS FPBA Inhibitor EIA Ex. U¹ U³ U⁴ IC₅₀ (μM) IC₅₀ (μM)  1 NHN CH 0.25 0.012 44 NBn CH N 15 (Step B) 44 NH CH N 2.8 45 CH N NH 1.5 46O N CH 125 47 O CH N >20 48 N S CH >20 49 NH N N 1.0 0.084

Example 44 Preparation of2-phenyl-5-(5-phenyl-1H-imidazol-2-yl)pyrimidine

Step A: Preparation of 1-benzyl-5-phenyl-1H-imidazole

The title intermediate was prepared by the method described in Example1, Step C, except that (i) commercially available bromobenzene was usedinstead of 5-bromo-2-phenylpyrimidine, and (ii) 1-benzyl-1H-imidazolewas used instead of 1-benzyl-2-phenyl-1H-imidazole. The product waspurified by flash silica column chromatography. Elution through a 25-gSilicycle® flash silica cartridge with gradient of 0% to 5% methanol indichloromethane afforded the title intermediate as a yellow solid (0.140g, 60% yield); R_(f) 0.53 with 9:1 v/v dichloromethane-methanol; ¹H-NMR(400 MHz; CDCl₃) δ 7.59 (s, 1H), 7.4-7.25 (m, 8H), 7.17 (s, 1H), 7.05(d, 2H), 5.18 (s, 2H); MS (ESI⁺) m/z 235.1 (M+1).

Step B: Preparation of5-(1-benzyl-5-phenyl-1H-imidazol-2-yl)-2-phenylpyrimidine

The title intermediate was prepared by the method described in Example1, Step C, except that (i) 1-benzyl-5-phenyl-1H-imidazole was usedinstead of 1-benzyl-2-phenyl-1H-imidazole, (ii) copper iodide (2.0 molarequivalents) and N,N-dimethylacetamide (15 mL) was used instead oftris(2-furyl)phosphine, potassium carbonate, and N,N-dimethylformamide.The reaction mixture was brought to reflux (160° C.) under a nitrogenatmosphere overnight and then worked up in the same manner as describedin Example 1, Step C to afford the title intermediate as a white solid(0.110 g, 35% yield); R_(f) 0.66 with 95:5 v/v dichloromethane-methanol;¹H-NMR (400 MHz; CDCl₃) δ 9.00 (s, 2H), 8.43 (m, 2H), 7.58-7.23 (m,12H), 5.35 (s, 2H); MS (ESI⁺) m/z 389.1 (M+1); —PGDS FPBA IC₅₀: 15 μM.

Step C: Preparation of 2-phenyl-5-(5-phenyl-1H-imidazol-2-yl)pyrimidine

The title compound was prepared by the method described in Example 1,Step D, except that5-(1-benzyl-5-phenyl-1H-imidazol-2-yl)-2-phenylpyrimidine (this Example,Step B) was used instead of5-(1-benzyl-2-phenyl-1H-imidazol-5-yl)-2-phenylpyrimidine. The titlecompound was isolated as a white solid (0.044 g, 62% yield); R_(f) 0.26with 95:5 v/v dichloromethane-methanol; melting point 238° C.; ¹H-NMR(400 MHz; DMSO-d₆) δ 9.40 (s, 2H), 8.43 (m, 2H), 7.99-7.84 (m, 2H),7.58-7.20 (m, 8H); MS (ESI⁺) m/z 299.1 (M+1); H-PGDS FPBA IC₅₀: 2.8 μM.

Example 45 Preparation of2-phenyl-5-(3-phenyl-1H-pyrazol-5-yl)pyrimidine

A mixture consisting of methyl 2-phenylpyrimidine-5-carboxylate (214 mg,1.00 mmol) and acetophenone (0.115 mL, 120 mg, 1.00 mmol) in diethylether (10 mL) under a nitrogen atmosphere at room temperature wasstirred for ten minutes. Sodium methoxide (65 mg, 1.2 mmol) wassubsequently added followed by methanol (1.0 mL). The solution wasstirred overnight at room temperature. The off-white precipitate whichhad formed was collected by filtration and was washed with diethylether. The solid was dissolved in water and the pH adjusted to 3 usingacetic acid. A solid precipitated and was collected by filtration andwashed with water. The solid was dried under high vacuum and wassubsequently dissolved in acetic acid (10 mL). To this solution wasadded hydrazine (0.4 mL) and the mixture was stirred at room temperatureovernight. The mixture was filtered and solids washed with hexane. Thecrude solid was purified by silica gel flash chromatography (9:1 to 1:1v/v hexane-ethyl acetate gradient) through a 25-g Silicycle® flashsilica cartridge which gave the title compound as light yellow solid (8mg, 3% yield); R_(f) 0.40 with 7:3 v/v hexane-ethyl acetate; ¹H-NMR (300MHz; CDCl₃) δ 9.38 (s, 2H), 8.45 (dd, 2H), 7.84 (br, 2H), 7.36-7.60 (m,7H); MS (ESI⁺) m/z 299 (M+1); H-PGDS FPBA IC₅₀: 1.5 μM.

Example 46 Preparation of 2-phenyl-5-(2-phenylpyrimidin-5-yl)oxazole

Silver carbonate (317 mg, 1.15 mmol), triphenylphosphine (16 mg, 0.06mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (24 mg, 5 mole %) were stirred together atroom temperature under nitrogen. 5-Bromo-2-phenylpyrimidine (163 mg,0.69 mmol) was added followed by 2-phenyl-oxazole (84 mg, 0.58 mmol;prepared according to Ohnmacht, S. A. et al., Chemical Communications,2008, 1241-1243). Finally water (6 mL) was added and the mixture heatedfor 18 hours at 60° C. The mixture was cooled to room temperature andfiltered through Celite washing with DCM and acetone. Purification bysilica gel flash chromatography (100% DCM) through a 12-g Silicycle®flash silica cartridge gave title compound as light yellow solid (19 mg,11% yield); R_(f) 0.68 with DCM; melting point 228-231° C.; ¹H-NMR (300MHz; DMSO-d₆) δ 9.39 (s, 2H), 8.45 (dd, 2H), 8.17 (dd, 2H), 8.11 (s,1H), 7.54-7.65 (m, 6H); MS (ESI⁺) m/z 300 (M+1), (ESI⁻) m/z 298 (M−1);H-PGDS FPBA IC₅₀: 125 μM.

Example 47 Preparation of 5-phenyl-2-(2-phenylpyrimidin-5-yl)oxazole

Step A: Preparation ofN-(2-oxo-2-phenylethyl)-2-phenylpyrimidine-5-carboxamide

To a solution consisting of 2-phenylpyrimidine-5-carboxylic acid (200mg, 1.0 mmol) in thionyl chloride (10 mL) was added one drop of dry DMF.The solution was heated to reflux for four hours and was subsequentlyallowed to reach room temperature. Thionyl chloride was evaporated awayunder reduced pressure and to the residue was added toluene (2×30 mL),which was evaporated and the residue subjected to high vacuum to removeresidual thionyl chloride. The residue and 2-amino-1-phenylethanonehydrochloride (172 mg, 1.0 mmol) were dissolved in dichloromethane (10mL) followed by triethylamine (0.28 mL). The solution was stirred atroom temperature for 18 hours. The mixture was diluted withdichloromethane and was washed with water. The organic phase was driedwith anhydrous sodium sulfate, filtered, and concentrated. The residuewas recrystallized from ethyl acetate to afford title intermediate as awhite solid (183 mg, 57% yield); R_(f) 0.60 with 5% methanol indichloromethane; ¹H-NMR (300 MHz; DMSO-d₆) δ 9.33 (s, 2H), 8.48 (d, 2H),8.07 (d, 2H), 7.70 (brt, 1H), 7.59 (m, 6H), 4.89 (d, 2H); MS (ESI⁻) m/z316 (M−1).

Step B: Preparation of 5-Phenyl-2-(2-phenylpyrimidin-5-yl)oxazole

To a solution consisting ofN-(2-oxo-2-phenylethyl)-2-phenylpyrimidine-5-carboxamide (Step A, 80 mg,0.25 mmol) in POCl₃ (1.0 mL) was added pyridine (2.0 mL). The solutionwas heated at 70° C. for six hours and was subsequently allowed to coolto room temperature. The solution was diluted with ethyl acetate (10 mL)and poured into a chilled saturated aqueous sodium bicarbonate solution(40 mL). After stirring for 15 minutes, the mixture was extracted withethyl acetate (3×25 mL) and the combined organics were dried withanhydrous sodium sulfate, filtered, and concentrated. The residue waspurified by silica gel flash chromatography (0-5% methanol indichloromethane gradient) through a 40-g Silicycle® flash silicacartridge to afford the title compound as an off-white solid (49 mg, 65%yield); R_(f) 0.80 with 2% methanol in dichloromethane; ¹H-NMR (300 MHz;DMSO-d₆) δ 9.52 (s, 2H), 8.48 (dd, 2H), 7.99 (s, 1H), 7.94 (dd, 2H),7.43-7.60 (m, 6H); MS (ESI⁺) m/z 300 (M+1); H-PGDS FPBA IC₅₀: >20 μM.

Example 48 Preparation of 2-phenyl-4-(2-phenylpyrimidin-5-yl)thiazole

A mixture consisting of 2-bromo-1-(2-phenylpyrimidin-5-yl)ethanone(Example 14, Step B, 50 mg, 0.18 mmol), thiobenzamide (TCI America, 25mg, 0.18 mmol) and absolute ethanol (4 mL) in a capped scintillationvial was heated to near boiling for several minutes and was subsequentlyallowed to cool to room temperature. A white solid precipitated withinminutes. The precipitate was collected by vacuum filtration. Lightethanol rinse, suction, and drying under high vacuum at room temperatureafforded the title compound (26 mg, 46% yield) as an off-white solid;melting point 214.4-216.1° C.; ¹H-NMR (400 MHz; DMSO-d₆) δ 9.54 (s, 2H),8.54 (s, 1H), 8.47 (m, 2H), 8.08 (m, 2H), 7.62-7.54 (m, 6H); LC/MS(ESI⁺) m/z 316.1, (ESI⁻) m/z 337.2 (M−1+Na⁺); H-PGDS FPBA IC₅₀: >20 μM.

Triazole compounds of general structure 25 of the exemplary embodimentsmay be prepared according to the general synthetic route illustrated inScheme 7. Examples 49 and 50 may be prepared using this general route.

Example 49 Preparation of2-phenyl-5-(5-phenyl-4H-1,2,4-triazol-3-yl)pyrimidine

2-Phenyl-pyrimidine-5-carbonitrile (Biofine International, 0.10 g, 0.55mmol) and benzoic hydrazide (Aldrich, 0.075 g, 0.55 mmol) were dissolvedin o-xylene (5 mL) and heated to 200° C. in a sealed pressure tube whilestirring for 24 hours. After cooling to room temperature, the reactionmixture was heated to 200° C. in an open vessel under a stream ofnitrogen for six hours. The remaining crude solid was dissolved in aminimal amount of 98:2 v/v dichloromethane-methanol and purified byflash silica column chromatography. Elution through a 40-g Analogix®flash silica cartridge with 100% dichloromethane to 2% methanol indichloromethane afforded the title compound as a pale yellow solid (10mg, 6% yield); R_(f) 0.1 with 98:2 v/v dichloromethane-methanol; meltingpoint 280-282° C.; ¹H-NMR (400 MHz; CDCl₃) δ 8.48-8.42 (m, 2H),8.12-8.06 (m, 2H), 7.60-7.48 (m, 6H); MS (ESI⁺) m/z 300.1 (M+1); H-PGDSFPBA IC₅₀: 1.0 μM; H-PGDS inhibitor EIA IC₅₀: 0.084 μM.

Example 50 Preparation of2-phenyl-5-(5-(pyridin-3-yl)-1H-1,2,4-triazol-3-yl)pyrimidine

2-Phenyl-pyrimidine-5-carbonitrile (Biofine International, 0.20 g, 1.10mmol) and nicotinic hydrazide (Aldrich, 0.151 g, 1.10 mmol) weredissolved in o-xylene (5 mL) and heated to 200° C. under nitrogenatmosphere for seven hours as the o-xylene slowly boiled off. Theremaining crude solid was dissolved in a minimal amount of 98:2 v/vdichloromethane-methanol and purified by flash silica columnchromatography. Elution through a 40-g Analogix® flash silica cartridgewith 100% dichloromethane to 5% methanol in dichloromethane afforded thetitle compound as a yellow solid (32 mg, 10% yield); R_(f) 0.27 with95:5 v/v dichloromethane-methanol; melting point 322-333° C.; ¹H-NMR(400 MHz; CDCl₃) δ 9.53 (s, 2H), 9.32 (d, 1H), 8.76-8.75 (m, 1H),8.53-8.46 (m, 3H), 7.64-7.60 (m, 4H); MS (ESI⁺) m/z 301.1 (M+1); H-PGDSFPBA IC₅₀: 1 μM.

Example 51 Preparation of5-(1-methyl-5-(pyridin-3-yl)-1H-1,2,4-triazol-3-yl)-2-phenylpyrimidine

2-Phenyl-5-(5-(pyridin-3-yl)-1H-1,2,4-triazol-3-yl)pyrimidine (25 mg,0.08 mmol) was dissolved in DMF (2 mL). An excess of sodium hydride (150mg, 60% dispersion in mineral oil) and an excess of iodomethane (1 mL)were added and the solution was stirred at room temperature for 2.5hours. The reaction was quenched by the addition of water, diluted withethyl acetate, and washed sequentially with water and brine. The cruderesidue was dissolved in a minimal amount of dichloromethane andpurified by flash silica column chromatography. Elution through a 12-gAnalogix® flash silica cartridge with 100% dichloromethane to 4%methanol in dichloromethane afforded the title compounds (2 mg, 8%yield); R_(f) 0.33 with 95:5 v/v dichloromethane-methanol; MS (ESI⁺) m/z315.1 (M+1).

Example 52 Preparation of tert-butyl4-(5-(2-phenylpyrimidin-5-O-2H-tetrazol-2-yl)piperidine-1-carboxylate

To a solution consisting of 2-phenyl-5-(2H-tetrazol-5-yl)pyrimidine (25mg, 0.111 mmol) in DMF (2.0 mL) was added tert-butyl4-(tosyloxy)piperidine-1-carboxylate (40 mg, 0.111 mmol), synthesizedfrom tert-butyl 4-hydroxypiperidine-1-carboxylate (PCT InternationalApplication No. WO 2007/060026), and sodium carbonate (85 mg, 0.45mmol). The suspension was vigorously stirred for 24 hours and anadditional molar equivalent of tert-butyl4-(tosyloxy)piperidine-1-carboxylate was added and the reaction washeated for another 24 hours at 70° C. After cooling to room temperature,the crude reaction mixture was diluted with ethyl acetate, washedsequentially with 1 M sodium carbonate, 5% citric acid, and brine. Aftersolvent evaporation, the remaining crude solid was dissolved in aminimal amount of dichloromethane and purified by flash silica columnchromatography. Elution through a 40-g Analogix® flash silica cartridgewith 100% dichloromethane to 2% methanol in dichloromethane provided thetitle compound as an off-white solid. The solid was further purified bytriturating with methanol to afford the title compound as a white solid(15 mg, 33% yield); R_(f) 0.37 with 95:2 v/v dichloromethane-methanol;melting point 178-180° C.; ¹H-NMR (400 MHz; CDCl₃) δ 9.47 (s, 2H),8.52-8.49 (m, 2H), 7.52-7.50 (m, 3H), 4.96-4.95 (m, 2H), 4.23 (bs, 2H),3.10-2.97 (m, 2H), 2.30-2.21 (m, 4H), 1.48 (s, 9H); MS (ESI⁺) m/z 408.2(M+1).

H-PGDS H-PGDS FPBA Inhibitor EIA Ex. R² W IC₅₀ (μM) IC₅₀ (μM) 41 H bond2.4 45 Ph bond 1.5 53 3-pyridyl bond 1.3 54 CO₂Et O 1.3 0.13 55 CO₂Me O2 56 CO₂H O 5 57

O 0.65 0.42

Example 53 Preparation of2-phenyl-5-(3-(pyridin-3-yl)-1H-pyrazol-5-yl)pyrimidine

To a solution consisting of 1-(2-phenylpyrimidin-5-yl)ethanone (Example14, Step A, 46 mg, 0.23 mmol) and methyl nicotinate (35 mg, 0.25 mmol)in tetrahydrofuran (1 mL) was added a solution consisting of potassiumtert-butoxide in tetrahydrofuran (0.28 mL, 0.28 mmol). The reactionmixture was stirred overnight. Analysis of the reaction mixture by TLC(1:3 ethyl acetate-hexanes) showed the1-(2-phenylpyrimidin-5-yl)ethanone was not consumed. To the reactionmixture was added methyl nicotinate (118 mg, 0.86 mmol) and sodiumhydride (10 mg, 0.23 mmol, 60% dispersion), and the reaction mixture washeated at 50° C. for one hour. The reaction mixture was diluted with asaturated aqueous solution of ammonium chloride and sodium chloride andthe organic material was extracted three times with ethyl acetate. Thecombined organic phase was dried over magnesium sulfate, filtered andconcentrated to dryness to provide a crude material. To a solutionconsisting of this crude material in acetic acid was added excesshydrazine hydrate and the reaction mixture was heated at 50° C. for twohours followed by 80° C. overnight. The reaction mixture was dilutedwith saturated aqueous sodium bicarbonate and the organic material wasextracted three times with ethyl acetate. The combined organic phase wasdried over magnesium sulfate, filtered, and concentrated to dryness. Thecrude material was chromatographed on silica (4 g) eluted with 1:4:5 v/vdichloromethane-ethyl acetate-hexane to 1:6:4 to afford the titlecompound (10 mg) as a tan solid; H-PGDS FPBA IC₅₀: 1.3 μM.

Example 54 Preparation of ethyl5-(2-phenoxypyrimidin-5-yl)-1H-pyrazole-3-carboxylate

Step A: Preparation of ethyl 3-oxo-3-(2-phenoxypyrimidin-5-yl)propanoate

A mixture consisting of 1-(2-phenoxypyrimidin-5-yl)ethanone (Example 38,Step B, 214 mg, 1.00 mmol) and diethyl oxalate (0.14 mL, 150 mg, 1.0mmol) in diethyl ether (10 mL) under a nitrogen atmosphere at roomtemperature was stirred for ten minutes. Sodium methoxide (65 mg, 1.2mmol) was subsequently added followed by methanol (1.0 mL). The solutionwas stirred overnight at room temperature. The off-white precipitatewhich had formed was collected by filtration and washed with diethylether. The solid was dissolved in water and the pH adjusted to 3 usingacetic acid. The solid precipitate which formed was filtered and washedwith water. The solid was air dried to afford a mixture comprising boththe ethyl and methyl esters.

Step B: Preparation of ethyl5-(2-phenoxypyrimidin-5-yl)-1H-pyrazole-3-carboxylate

To a mixture consisting of the solid comprising ethyl3-oxo-3-(2-phenoxypyrimidin-5-yl)propanoate (Step A, 1.00 mmol theory)in acetic acid (10 mL) was added hydrazine (0.40 mL, 410 mg, 13 mmol).The stirring mixture was heated to 60° C. for one hour and wassubsequently cooled to room temperature and stirred overnight. Theoff-white solid which had precipitated was collected by filtration andwashed with hexane. The solid was purified by silica gel flashchromatography using a 9:1 to 1:1 v/v hexane-ethyl acetate gradientthrough a 40-g Silicycle® flash silica cartridge to afford the titlecompound as a white solid (100 mg, 32% yield); R_(f) 0.50 with 1:1 v/vhexane-ethyl acetate; ¹H-NMR (300 MHz; DMSO-d₆) δ 9.12 (s, 2H), 7.50 (s,1H), 7.43 (dd, 2H), 7.20-7.28 (m, 3H), 4.26 (q, 2H), 1.25 (t, 3H); MS(ESI⁻) m/z 309 (M−1); H-PGDS FPBA IC₅₀: 1.3 μM; H-PGDS inhibitor EIAIC₅₀: 0.13 μM.

Example 55 Preparation of methyl5-(2-phenoxypyrimidin-5-yl)-1H-pyrazole-3-carboxylate

The title compound was isolated from the chromatography of Example 54,Step B as white solid (52 mg, 17% yield); R_(f) 0.40 with 1:1 v/vhexane-ethyl acetate; ¹H-NMR (300 MHz; DMSO-d₆) δ 9.08 (s, 2H), 7.50 (s,1H), 7.46 (dd, 2H), 7.20-7.30 (m, 3H), 3.90 (s, 3H); MS (ESI⁻) m/z 309(M−1); H-PGDS FPBA IC₅₀: 2 μM.

Example 56 Preparation of5-(2-phenoxypyrimidin-5-yl)-1H-pyrazole-3-carboxylic acid

To a solution consisting of lithium hydroxide monohydrate (0.13 g, 3.0mmol) dissolved in ethanol (10 mL)/water (5 mL) was added ethyl5-(2-phenoxypyrimidin-5-yl)-1H-pyrazole-3-carboxylate (Example 54, 90mg, 0.29 mmol) and the mixture was stirred at room temperature for 18hours. Ethanol was removed under reduced pressure and the solutiondiluted with water and subsequently was acidified with acetic acid toprecipitate product. The solid precipitate was filtered, washed withwater, and dried under high vacuum to afford the title compound as awhite solid (64 mg, 79% yield); R_(f) 0.15 with 2% methanol indichloromethane; ¹H-NMR (300 MHz; DMSO-d₆) δ 9.12 (s, 2H), 7.49 (dd,2H), 7.25-7.43 (m, 4H); MS (ESI⁻) m/z 281 (M−1); H-PGDS FPBA IC₅₀: 5 μM.

Example 57 Preparation of(4-methylpiperazin-1-yl)(5-(2-phenoxypyrimidin-5-yl)-1H-pyrazol-3-yl)methanone

To a solution consisting of5-(2-phenoxypyrimidin-5-yl)-1H-pyrazole-3-carboxylic acid (Example 56,60 mg, 0.21 mmol) in thionyl chloride (10 mL) was added one drop of dryDMF. The solution was heated to reflux for four hours and wassubsequently allowed to cool to room temperature. Thionyl chloride wasevaporated under reduced pressure and to the residue was added toluene(2×30 mL), which was evaporated and the residue subjected to high vacuumto remove residual thionyl chloride. The residue and 1-methylpiperazine(25 mg, 0.028 mL, 0.25 mmol) were dissolved in dichloromethane (10 mL)followed by the addition of triethylamine (0.14 mL). The solution wasstirred at room temperature for 18 hours. The solvent was evaporated andthe residue was purified by silica gel flash chromatography using 0-10%methanol in dichloromethane gradient through a 25-g Silicycle® flashsilica cartridge to afford the title compound as a white solid (46 mg,60% yield); R_(f) 0.30 with 6% methanol in dichloromethane; ¹H-NMR (300MHz; CD₃OD) δ 8.96 (s, 2H), 7.43 (m, 2H), 7.25 (m, 1H), 7.19 (d, 2H),7.02 (s, 1H), 3.74-3.99 (br, 4H), 2.51 (br, 4H), 2.33 (s, 3H); MS (ESI⁻)m/z 363 (M−1); H-PGDS FPBA IC₅₀: 0.65 μM; H-PGDS inhibitor EIA IC₅₀:0.42 μM.

H-PGDS H-PGDS FPBA Inhibitor EIA Ex. R² IC₅₀ (μM) IC₅₀ (μM)   48 Ph >2058 3-F—Ph >20 59 3-pyridyl 1 0.15 60 PhCH₂— >20 61

5

Example 58 Preparation of2-(3-fluorophenyl)-4-(2-phenylpyrimidin-5-yl)thiazole

The title compound was prepared according to the procedure described inExample 48 except that 3-fluorothiobenzamide was used instead ofthiobenzamide. The title compound was isolated (35.4 mg, 59% yield) as awhite solid; melting point 228° C.; ¹H-NMR (400 MHz; DMSO-d₆) δ 8.62 (s,2H), 8.48-8.53 (m, 3H), 7.94-8.01 (m, 2H), 7.58-7.70 (m, 4H), 7.42-7.48(m, 1H); LC/MS (ESI⁺) m/z 334; H-PGDS FPBA IC₅₀: >20 μM.

Example 59 Preparation of4-(2-phenylpyrimidin-5-yl)-2-(pyridin-3-yl)thiazole

The title compound was prepared according to the procedure described inExample 48 except that thionicotinamide was used instead ofthiobenzamide. The title compound was isolated (30.2 mg, 53% yield) asan off-white solid; melting point 319° C.; ¹H-NMR (400 MHz; DMSO-d₆) δ9.39 (s, 2H), 9.38 (s, 1H), 8.81-8.84 (m, 1H), 8.69 (s, 1H), 8.59-8.64(m, 1H), 8.48-8.54 (m, 2H), 7.72-7.77 (m, 1H), 7.59-7.64 (m, 3H); LC/MS(ESI⁺) m/z 317; H-PGDS FPBA IC₅₀: 1 μM; H-PGDS inhibitor EIA IC₅₀: 0.15μM.

Example 60 Preparation of 2-benzyl-4-(2-phenylpyrimidin-5-yl)thiazole

The title compound was prepared according to the procedure described inExample 48 except that 2-phenylthioacetamide was used instead ofthiobenzamide. The title compound was isolated (26 mg, 51% yield) as apale yellow solid; melting point 170° C.; ¹H-NMR (400 MHz; DMSO-d₆) δ9.45 (s, 2H), 8.45-8.50 (m, 2H), 8.36 (s, 1H), 7.57-7.62 (m, 3H),7.31-7.48 (m, 5H), 4.50 (s, 2H); LC/MS (ESI⁺) m/z 330; H-PGDS FPBAIC₅₀: >20 μM.

Example 61 Preparation of4-(4-(2-phenylpyrimidin-5-yl)thiazol-2-yl)piperidinium2,2,2-trifluoroacetate

Step A: Preparation of tert-butyl4-(4-(2-phenylpyrimidin-5-yl)thiazol-2-yl)piperidine-1-carboxylate

The title intermediate was prepared according to the procedure describedin Example 48 except that tert-butyl4-(aminocarbothioyl)tetrahydropyridine-1(2H)-carboxylate was usedinstead of thiobenzamide. The product was isolated (27 mg) as anoff-white solid; LC/MS shows a mixture of title intermediate ((ESI⁺) m/z423) and title (deprotected) compound ((ESI⁺) m/z 323).

Step B: Preparation of4-(4-(2-phenylpyrimidin-5-yl)thiazol-2-yl)piperidinium2,2,2-trifluoroacetate

A mixture consisting of title intermediate (23 mg) and trifluoroaceticacid (500 μL) was stirred at room temperature for 20 minutes. Thetrifluoroacetic acid was removed yielding an off-white oil. Triturationwith ethanol produced an off-white solid which was subsequently filteredand washed with ethanol to afford the title compound (23.5 mg, 85%yield) as a white solid; melting point 290° C.; ¹H-NMR (400 MHz;DMSO-d₆) δ 9.50 (s, 2H), 8.50-8.58 (m, 2H), 8.45 (s, 1H), 7.60-7.65 (m,3H), 3.32-3.59 (m, 4H), 3.08-3.20 (m, 2H), 2.30-2.39 (m, 2H), 1.94-2.07(m, 2H); LC/MS (ESI⁺) m/z 323; H-PGDS FPBA IC₅₀: 5 μM.

H-PGDS H-PGDS FPBA Inhibitor EIA Ex. R² IC₅₀ (μM) IC₅₀ (μM) 62 CO₂^(t)Bu 5.9 63 CO₂H 1.1 64

3.4 65

2.5

Example 62 Preparation of 2 tert-butyl2-(2-phenylpyrimidin-5-yl)thiazole-4-carboxylate

In a sealed tube, cesium carbonate (1.95 g, 6.00 mmol),tert-butyl-4-thiazolecarboxylate (556 mg, 3.00 mmol; prepared accordingto the procedure described in Organic Letters, 2008, 10(13), 2909),palladium(II) acetate (47 mg, 0.21 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (240 mg, 0.42 mmol) werecombined with 5-bromo-2-phenylpyrimidine (705 mg, 3.00 mmol) in dry DMF(11 mL) and the mixture heated at 110° C. for 18 hours with stirring.The mixture was cooled to room temperature and filtered through Celitewashing with hot ethyl acetate. Solvent was removed under reducedpressure and the residue purified by silica gel flash chromatography(9:1 to 3:2 v/v hexane-ethyl acetate gradient) through a 40-g Silicycle®flash silica cartridge. The title compound was obtained as a white solid(646 mg, 63% yield); R_(f) 0.75 with 1:1 v/v hexane-ethyl acetate;¹H-NMR (300 MHz; CDCl₃) δ 9.37 (s, 2H), 8.52 (dd, 2H), 8.15 (s, 1H),7.54 (m, 3H), 1.64 (s, 9H); MS (ESI⁺) m/z 340 (M+1); H-PGDS FPBA IC₅₀:5.9 μM.

Example 63 Preparation of2-(2-Phenylpyrimidin-5-yl)thiazole-4-carboxylic acid

To a solution consisting of lithium hydroxide monohydrate (0.38 g, 9.0mmol) dissolved in ethanol (20 mL)/water (10 mL) was added tert-butyl2-(2-phenylpyrimidin-5-yl)thiazole-4-carboxylate (Example 62, 705 mg,3.0 mmol) in dry DMF (11 mL) and the mixture stirred at room temperaturefor 18 hours. Ethanol was removed under reduced pressure and thesolution diluted with water and subsequently extracted with diethylether (2×30 mL). The aqueous phase was acidified with 2 N hydrochloricacid to pH2. The solid precipitate was filtered, washed with water anddried under high vacuum to give the title compound as an off-white solid(371 mg, 87% yield); R_(f) 0.15 with 9:1 v/v dichloromethane-methanol;¹H-NMR (300 MHz; DMSO-d₆) δ 9.39 (s, 2H), 8.63 (s, 1H), 8.44 (dd, 2H),7.55 (m, 3H); MS (ESI⁺) m/z 284 (M+1); H-PGDS FPBA IC₅₀: 1.1 μM.

Example 64 Preparation ofN-(3-methoxypropyl)-2-(2-phenylpyrimidin-5-yl)thiazole-4-carboxamide

To a solution consisting of2-(2-phenylpyrimidin-5-yl)thiazole-4-carboxylic acid (Example 63, 80 mg,0.28 mmol) in dichloromethane (10 mL) was added EDAC (75 mg, 0.39 mmol)and HOBt (53 mg, 0.39 mmol) at 0° C. To this mixture was added3-methoxypropylamine (25 mg, 0.28 mmol) dissolved in dichloromethane (2mL) and diisopropylethylamine (0.52 mL, 390 mg, 3.0 mmol). The solutionwas allowed to reach room temperature and stirred for 18 hours. Thesolvent was evaporated away under reduced pressure and the residue waspurified by silica gel flash chromatography (1:1 v/v hexane-ethylacetate to 100% ethyl acetate gradient) through a 25-g Silicycle® flashsilica cartridge. The title compound was obtained as an off-white solid(21 mg, 21% yield); R_(f) 0.70 with 4:1 v/v ethyl acetate-hexane;melting point 134-136° C.; ¹H-NMR (300 MHz; CDCl₃) δ 9.31 (s, 2H), 8.52(dd, 2H), 8.20 (s, 1H), 7.88 (br t, 1H), 7.53 (m, 3H), 3.62 (t, 2H);3.59 (t, 2H); 3.41 (s, 3H), 1.96 (m, 2H); MS (ESI⁺) m/z 355 (M+1);H-PGDS FPBA IC₅₀: 3.4 μM.

Example 65 Preparation ofN-(2-morpholinoethyl)-2-(2-phenylpyrimidin-5-yl)thiazole-4-carboxamide

To a solution consisting of2-(2-phenylpyrimidin-5-yl)thiazole-4-carboxylic acid (Example 63, 172mg, 0.61 mmol) in thionyl chloride (10 mL) was added one drop of dryDMF. The solution was heated at reflux for four hours and wassubsequently allowed to reach room temperature and stirred for 18 hours.The thionyl chloride was evaporated away under reduced pressure and tothe residue was added toluene (2×30 mL), which was evaporated and theresidue subjected to high vacuum to remove residual thionyl chloride.The residue was dissolved in dichloromethane (10 mL) and4-(2-aminoethyl)morpholine (51 mg, 0.051 mL, 0.40 mmol) was addedfollowed by diisopropylethylamine (0.10 mL). The solution was stirred atroom temperature for 18 hours. The solvent was removed under reducedpressure and the residue partitioned between water and diethyl ether.The organics were dried with anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified by silica gel flashchromatography (100% dichloromethane to 9:1 v/v dichloromethane-methanolgradient) through a 40-g Silicycle® flash silica cartridge. The titlecompound was obtained as an off-white solid (63 mg, 61% yield); R_(f)0.70 with 9:1 v/v dichloromethane-methanol; ¹H-NMR (300 MHz; CDCl₃) δ9.30 (s, 2H), 8.51 (m, 2H), 8.20 (s, 1H), 7.88 (br t, 1H), 7.53 (m, 3H),3.77 (t, 4H); 3.61 (dt, 2H), 2.64 (t, 2H), 2.54 (t, 4H); MS (ESI⁺) m/z396 (M+1); H-PGDS FPBA IC₅₀: 2.5 μM.

Example 66 Preparation of2-methyl-5-(2-(pyridin-3-yl)-1H-imidazol-5-yl)pyridine

Step A: Preparation of5-(1-benzyl-2-(pyrimidin-3-yl)-1H-imidazol-5-yl)-2-methylpyridine

To a mixture consisting of 5-bromo-2-methylpyridine (Chem-Impex, 0.132g, 0.770 mmol), palladium (II) acetate (Strem, 0.022 g, 0.032 mmol),tris(2-furyl)phosphine (TCI America, 0.015 g, 0.064 mmol) and potassiumcarbonate (0.177 g, 1.283 mmol) was added a solution consisting of3-(1-benzyl-1H-imidazol-2-yl)pyridine (0.151 g, 0.642 mmol) inN,N-dimethylformamide (2 mL). The reaction mixture was brought to refluxat 140° C. while under a nitrogen atmosphere. After stirring for 16hours at reflux the solution was cooled to room temperature. Thereaction mixture was partitioned between ethyl acetate (120 mL) andsaturated aqueous ammonium chloride (50 mL). The phases were separatedand the organic layer was washed with brine (75 mL), and wassubsequently dried over anhydrous magnesium sulfate. Concentration underreduced pressure afforded the crude product as an orange oil. Theproduct was purified by flash silica column chromatography. Elutionthrough a 80-g Silicycle® flash silica cartridge with gradient of 2% to5% methanol in dichloromethane afforded the title intermediate (0.112 g,53% yield); R_(f) 0.2 with 5:95 v/v methanol-dichloromethane; MS (APCI⁺)m/z 327.3 (M+1); H-PGDS FPBA IC₅₀: >10 μM.

Step B: Preparation of2-methyl-5-(2-(pyridin-3-yl)-1H-imidazol-5-yl)pyridine

To a solution consisting of5-(1-benzyl-2-(pyridin-3-yl)-1H-imidazol-5-yl)-2-methylpyridine (0.112g, 0.343 mmol) in methanol (27 mL) was added ammonium formate (Aldrich,0.216 g, 12.7 mmol) and 10% palladium on carbon (Alfa Aesar, 0.135 g).The reaction mixture was brought to reflux at 70° C. for 16 hours. Aftercooling the solution to room temperature, the crude reaction mixture wasfiltered through a 45 μM syringe filter and was rinsed with additionalmethanol. Concentration of the filtrate afforded a yellow oil. Theproduct was purified by flash silica column chromatography and elutedthrough a 25-g Silicycle® flash silica cartridge with 10:90 v/vmethanol-dichloromethane. After combining all fractions containingproduct and removing the solvents, the title compound precipitated fromdichloromethane as a white solid (0.013 g, 16% yield); R_(f) 0.50 with90:10 v/v dichloromethane-methanol; melting point 237-239° C.; ¹H-NMR(400 MHz; MeOH-d₄) δ 9.11 (d, 1H), 8.85 (d, 2H), 8.56 (dd, 1H), 8.36 (m,1H) 8.13 (dd, 1H), 7.69 (s, 1H), 7.56 (m, 1H), 7.33 (d, 1H), 2.54 (s,3H); MS (ESI⁺); H-PGDS FPBA IC₅₀: >10 μM.

Example 67 Preparation ofphenyl(5-(2-(pyridin-3-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)methanone

The title compound is prepared by the method described in Example 1,except that (5-bromopyrimidin-2-yl)(phenyl)methanone (prepared accordingto the procedure described in WO 2008/121670 p. 94) is used instead of5-bromo-2-phenylpyrimidine and 3-(1-benzyl-1H-imidazol-2-yl)pyridine isused instead of 1-benzyl-2-phenyl-1H-imidazole in Step C.

Example 68 Preparation ofphenyl(5-(2-(pyridin-3-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)methanol

To a solution consisting ofphenyl(5-(2-(pyridin-3-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)methanone(Example 67) dissolved in methanol is added sodium borohydride (1 molarequivalent) at 0° C. The mixture is allowed to reach room temperatureand is stirred one hour. The mixture is partitioned between ethylacetate and water and the organics washed with brine, dried (Na₂SO₄),filtered and concentrated to afford the title compound.

Example 69 Preparation of2-phenyl-5-(2-(1-(pyridin-3-yl)piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine

The title compound is prepared in a similar manner as described inTetrahedron Letters, 2007, 48(14), 2519-2525. In this case, to adegassed solution of sodium tert-butoxide, palladium acetate, and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos) intert-butanol and toluene is added 3-bromopyridine and2-phenyl-5-(2-(piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine. The reactionis stirred and heated at 120° C. under nitrogen for 18 hours. Thereaction mixture is cooled, diluted with water and the organic materialis extracted with ethyl acetate. The organic phase is washed with brine,dried over magnesium sulfate, filtered and concentrated under reducedpressure. The residue is chromatographed on silica to give the titlecompound.

Example 70 Preparation of3-(4-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyridazine

The title compound is prepared in a similar manner described above usingBuchwald-Hartwig amination conditions or as described in PCTInternational Application 2006/058338, 1 Jun. 2006. In this case, asolution consisting of2-phenyl-5-(2-(piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine and6-chloropyridazine 1-oxide (preparation of this reagent can be found inPCT International Application 2007/106670, 20 Sep. 2007 and Chemical andPharmaceutical Bulletin, 1963, 11, 261-263) in dimethylsulfoxide isheated at 80° C. for 18 hours. The reaction mixture is cooled, dilutedwith water and the organic material is extracted with ethyl acetate. Theorganic phase is washed with brine, dried over magnesium sulfate,filtered and concentrated under reduced pressure. The residue ischromatographed on silica to afford the title compound.

Example 71 Preparation of5-(1-benzyl-2-(pyridin-3-yl)-1H-imidazol-5-yl)-4-methyl-2-phenylthiazole

The title compound was prepared by the method described in Example 1,except that (i) commercially available 5-bromo-4-methyl-2-phenylthiazole(Apollo Scientific) was used instead of 5-bromo-2-phenylpyrimidine inStep C, and (ii) 3-(1-benzyl-1H-imidazol-2-yl)pyridine was used insteadof 1-benzyl-2-phenyl-1H-imidazole in Step C.3-(1-Benzyl-1H-imidazol-2-yl)pyridine was prepared by the proceduredescribed in Example 8, Steps A and B except the commercially available3-cyanopyridine was used instead of 3-fluorobenzonitrile; R_(f) 0.34with 95:5 v/v dichloromethane-methanol; ¹H-NMR (400 MHz; DMSO-d₆) δ 8.87(dd, 1H), 8.64-8.63 (dd, 1H), 7.94-7.91 (m, 1H), 7.86-7.84 (m, 2H),7.43-7.22 (m, 8H), 6.83-6.81 (m, 2H), 5.25 (s, 2H), 2.31 (s, 3H); MS(ESI⁺) m/z 409.1 (M+1); H-PGDS FPBA IC₅₀: >20 μM.

Example 72 Preparation of4-methyl-2-phenyl-5-(2-(pyridin-3-yl)-1H-imidazol-5-yl)thiazole

The title compound is prepared from5-(1-benzyl-2-(pyridin-3-yl)-1H-imidazol-5-yl)-4-methyl-2-phenylthiazole(Example 71) in a similar manner as described in Tetrahedron Letters,2008, 64(26), 6060-6072. In this case,5-(1-benzyl-2-(pyridin-3-yl)-1H-imidazol-5-yl)-4-methyl-2-phenylthiazolein methanol is debenzylated by hydrogenation under an atmosphericpressure of hydrogen using a balloon with vigorous stirring for 70 hunder reflux. The reaction mixture is filtered through Celite, filteredand concentrated under reduced pressure. The residue is chromatographedon silica to give the title compound.

Tetrazole compounds with the general structures 24a and 24b of theexemplary embodiments may be prepared using the general synthetic routedescribed in Scheme 8.

Example 73 Preparation of5-(2-methyl-2H-tetrazol-5-yl)-2-phenylpyrimidine (A) and5-(1-methyl-1H-tetrazol-5-yl)-2-phenylpyrimidine (B)

The title compounds were prepared from2-phenyl-5-(1H-tetrazol-5-yl)pyrimidine (Example 43, 20 mg, 0.022 mmol)using iodomethane (500 μL, 8.0 mmol), triethylamine (330 μL, 2.37 mmol)in acetonitrile (3 mL). The reaction was heated to 40° C. for threehours. The reaction mixture was concentrated and purified by columnchromatography using a gradient of 100% dichloromethane to 1:99 v/vmethanol-dichloromethane affording the title compounds as white solids(73% total yield); Example 73A: 10.3 mg; melting point 228° C.; ¹H-NMR(400 MHz; CDCl₃) δ 9.49 (s, 2H), 8.51-8.54 (m, 2H), 7.52-7.54 (m, 3H),4.47 (s, 3H); LC/MS (ESI⁺) m/z 239; H-PGDS FPBA IC₅₀: 10 μM; Example73B: 3.1 mg; melting point 238° C.; ¹H-NMR (400 MHz; CDCl₃) δ 9.23 (s,2H), 8.54-8.56 (m, 2H), 7.55-7.57 (m, 3H), 4.30 (s, 3H); LC/MS (ESI⁺)m/z 239; H-PGDS FPBA IC₅₀: 20 μM.

Example 74 H-PG DS Fluorescence Polarization Binding Assay

This assay essentially is available from Cayman Chemical Company asCatalog item #600007. The test data reported for the aforementionedExamples (H-PGDS FPBA IC₅₀) were generated using a 96-well, instead ofthe 384-well, format.

Detection analyte and H-PGDS-MBP fusion enzyme were incubated in thepresence of reduced glutathione (5 mM) for 60-90 minutes at roomtemperature and FP was measured using a TECAN SAFIRE 2 plate readerequipped with absorbance, fluorescence, fluorescence polarization andFRET capabilities. Assays were performed in 96-well microtiter plates in100 μL of total sample volume. Excitation and emission wavelengthsappropriate for the employed detection analyte were used.

Step A: Preparation of Reagents (i). Detection Analyte: H-PGDS FPFluorescent Probe—Green

FP buffer concentrate (4× (200 mM Tris pH8.0, 200 mM KCl, 20 mM CHAPS,40 mM DTT), Cayman Chemical Catalog No. 600028, 6 mL) was diluted withdeionized water (18 mL) to provide 1×FP buffer (24 mL).

A solution consisting of2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-5-(2-(3-((2-phenylpyrimidine-5-carboxamido)methyl)phenylsulfonamido)ethylcarbamoyl)benzoicacid in absolute ethanol (20 μL, 100 ug/mL) was diluted with 1×FP buffer(180 μL) to provide the H-PGDS FP fluorescent probe—green reagent.

(ii). Enzyme: H-PGDS-MBP Fusion

H-PGDS-Maltose binding protein (MBP; 100 ul, 0.5 mg/ml) fusion wasdiluted with 1×FP buffer (900 μL).

(iii). HQL-79 FP Positive Control

Twelve clean microfuge tubes were labeled A1 through A12. A 5 mM4-(diphenylmethoxy)-1-[3-(1H-tetrazol-5-yl)propyl-piperidine (HQL-79) indimethyl sulfoxide (DMSO) solution (Cayman Chemical Catalog No. 600027,100 μL) was added to tube A12. Dimethyl sulfoxide (50 μL) was added toeach of tubes A1 through A11. The HQL-79 control solution was seriallydiluted by removing 50 μL from tube A12 and placing it in tube A11 withsubsequent thorough mixing of the contents of tube A11. Next, 50 μL wasremoved from tube A11 and was placed into tube A10 with subsequentthorough mixing of the contents of tube A10. This process was repeatedfor tubes A9 through A2.

(iv). Glutathione (GSH) Solution

A 100 mM aqueous (deionized water) glutathione solution (1,500 μL invial) was obtained from Cayman Chemical Company (Catalog No. 600029).

Step B: Preparation of Assay Cocktail

Into a 50 mL conical tube was added the H-PGDS 1× FP buffer (18.65 mL),H-PGDS FP fluorescent probe—green (138 μL), H-PGDS-MBP fusion dilution(880 μL), and glutathione solution (1,250 μL). The cocktail prepared wasenough for either a standard 96-well, 384-well, or higher density plate.

Step C: Preparation of Test Compound Solutions

A test compound may be dissolved in DMSO, ethanol, or methanol atseveral concentrations when the titration endpoint is unknown. A finalvolume of 5 μL is added to each inhibitor well.

Step D: Assay Protocol (96-Well Plate Format) (i). Apportionment of theAssay Cocktail

Assay cocktail (95 μL) was added to each plate well.

(ii). Preparation of Maximum Binding (100% Activity) Wells

DMSO (5 μL) from microfuge tube A1 was added to each plate well A1 andB1.

(iii). Apportionment of HQL-79 Positive Control Solution

Positive control solution (5 μL) from microfuge tube A2 was added toeach plate well A2 and B2. Positive control solution (5 μL) frommicrofuge tube A3 was added to each plate well A3 and B3. This procedurewas continued until all the positive control standard dilutions werealiquoted.

(iv). Apportionment of Test Compound Solutions

Test compound solutions (5 μL) were added to the wells. Each testcompound concentration was typically assayed in duplicate or triplicate.The IC₅₀ for a particular test compound was obtained by performing afull concentration titration versus a full concentration titration ofpositive control. Comparison of a single concentration of a testcompound to the maximum binding well provided an assessment of therelative affinity of the test compound for H-PGDS-MBP.

(v). Incubation

The plate was covered and incubated for 60-90 minutes at roomtemperature. The FP signal is stable for at least two hours.

(vi). Plate Reading

Plates were read with excitation and emission wavelengths of 470 nm and530 nm (for detection analyte comprising the fluorescein fluorophore),respectively. The measurements were taken in the fluorescentpolarization mode with the z-height set to the middle of the well andthe G-factor set to 1.13 on a Tecan Safire 2 reader.

Example 75 H-PGDS Inhibitor Enzyme Immunoassay

The assay detects and measures PGD₂ generated by H-PGDS. The prostanoidproduct is quantified via enzyme immunoassay (EIA) using a specific PGD₂antibody.

The assay is carried out by the following steps:

-   -   1. Inhibitor screening is performed in 100 mM Tris-HCl, pH 8.0        containing 1 mM GSH, 1 mM MgCl₂, 4% inhibitor/DMSO, 40 μM PGH₂        and 25 ng of PGDS in a total volume of 125 μL.    -   2. A reaction mixture containing 100 mM Tris-HCl, pH 8.0, 1 mM        GSH, 1 mM MgCl₂, 25 ng H-PGDS and 4% inhibitor or DMSO        (uninhibited reaction) is preincubated at 25° C. for 10 minutes.    -   3. Reactions are initiated using 5 μL of PGH₂ and quenched every        15 seconds for one minute. Reactions are quenched by taking 10        μL of reaction mixture and adding to 490 μL of 100 mM phosphate        buffer containing 0.1% BSA, 400 mM NaCl, 1 mM EDTA, 20 mM FeCl₂,        10% 1N HCl, and 0.01% azide to prevent the non-enzymatic        formation of PGD₂ from PGH₂. The FeCl₂ serves the purpose of        reducing PGH₂ to 12-HHT. (Quench buffer is kept on ice at all        times).    -   4. Quenched samples (5 μL) are further diluted 100 fold in 495        μL of 100 mM phosphate buffer containing 0.1% BSA, 400 mM NaCl,        1 mM EDTA, and 0.01% azide for the PGD₂ EIA assay. (Dilution        buffers are kept on ice at all times).

The final 5000 fold diluted samples are analyzed following the protocoloutlined in Cayman Chemical's commercially available PGD₂ EIA kit (Cat.#512021). 50 μL of diluted sample is analyzed at least in duplicate inthe EIA assay and the amount of PGD₂ formed is quantified using astandard curve.

Other exemplary embodiments of the invention will become apparent fromthe detailed description provided hereinafter. It should be understoodthat the detailed description and specific examples, while disclosingexemplary embodiments of the invention, are intended for purposes ofillustration only and are not intended to limit the scope of theinvention.

1.-60. (canceled)
 61. A compound of Formula (II):

wherein: R¹ is (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, phenyl, 2-pyridyl,3-pyridyl, or 4-pyridyl; wherein each phenyl, 2-pyridyl, 3-pyridyl, or4-pyridyl of R¹ may be optionally substituted with no more than two ofeach or a combination of fluoro, hydroxy, —CH₂OH, carboxy,carboxymethyl, or carboxyethyl; R² is —(CH₂)_(n)Z¹ or —(CH₂)_(n)Z²; n is0, 1, 2, 3, or 4; Z¹ is hydrogen, OR³, C(O)R³, CO₂R³, C(O)NR⁴R⁵,SO₂NR⁴R⁵, SO₂R³, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, (C₃-C₆)-alkenyl,(C₃-C₆)-alkynyl, (C₆-C₁₄)-aryl, (CH₂)_(p)CF₃, a five- to ten-memberedheteroaryl,

or a three- to ten-membered heterocycle; wherein any one nitrogen atomof any heterocycle containing one or more nitrogen atoms that may besubstituted with a non-ring atom are substituted with —(CH₂)_(q)Q; Z² iscyano, trifluoromethyl, (CF₂)_(p)CF₃, SR³, NR⁴R⁵, N(H)C(O)R³, N(H)CO₂R³,N(H)C(O)NR⁴R⁵, N(H)SO₂R³, vinyl, or ethynyl when n is 1, 2, 3 or 4; Z²may also be cyano, trifluoromethyl, (CF₂)_(p)CF₃, SR³, NR⁴R⁵,N(H)C(O)R³, N(H)CO₂R³, N(H)C(O)NR⁴R⁵, N(H)SO₂R³, vinyl, or ethynyl whenn is 0, except when R² is covalently bonded to a U¹, U², U³, or U⁴ thatis a nitrogen atom; R³ is hydrogen, (C₁-C₆)-alkyl, trifluoromethyl,(C₃-C₆)-alkenyl, (C₃-C₆)-alkynyl, (CH₂)_(m)(C₃-C₆)-cycloalkyl,(CH₂)_(m)phenyl, (CH₂)_(m)-(five- to ten-membered heteroaryl), or(CH₂)_(m)(three- to ten-membered heterocycle); wherein any one nitrogenatom of any heterocycle containing one or more nitrogen atoms that maybe substituted with a non-ring atom are substituted with —(CH₂)_(q)Q; mis 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; Q is hydrogen,(C₁-C₆)-alkyl, (CH₂)_(p)CF₃, (C₃-C₆)-alkenyl, (C₃-C₆)-alkynyl,(C₃-C₆)-cycloalkyl, (C₆-C₁₄)-aryl, C(O)R³, CO₂R³, C(O)NR⁴R⁵, a three- tosix-membered heterocycle, or a five- to ten-membered heteroaryl when qis 0, 1, 2, 3, or 4; Q may also be cyano, trifluoromethyl, or SO₂NR⁴R⁵when q is 1, 2, 3, or 4; Q may also be hydroxy, (C₁-C₆)-alkoxy,sulfhydryl, —S—(C₁-C₆)-alkyl, or NR⁴R⁵ when q is 2, 3, or 4; p is 1, 2,or 3; R³ may also be vinyl or ethynyl when R³ is not covalently bondedto an N or O atom; R³ may also be vinyl or ethynyl when R³ is notcovalently bonded to an S atom possessing a −2 (minus 2) oxidationstate; R⁴ and R⁵ are independently hydrogen, (C₁-C₆)-alkyl,(C₃-C₆)-alkenyl, (C₃-C₆)-alkynyl, (CH₂)_(m)(C₃-C₆)-cycloalkyl,(CH₂)_(m)phenyl, (CH₂)_(m)-(three- to ten-membered heterocycyl), or(CH₂)_(m)-(five- to ten-membered heteroaryl); the NR⁴R⁵ group of anyC(O)NR⁴R⁵, SO₂NR⁴R⁵, NR⁴R⁵, or N(H)C(O)NR⁴R⁵ may also form apyrrolidine, a piperidine, a morpholine, a thiomorpholine, or athiomorpholine S-dioxide; the NR⁴R⁵ group of any C(O)NR⁴R⁵, SO₂NR⁴R⁵,NR⁴R⁵, or N(H)C(O)NR⁴R⁵ may also form a piperazine ring, wherein theother nitrogen atom of the piperazine ring is substituted with hydrogen,(C₁-C₆)-alkyl, CH₂CF₃, (C₃-C₆)-cycloalkyl, CH₂(C₃-C₆)-cycloalkyl,phenyl, benzyl, hydroxyethyl, or hydroxypropyl; phenyl or heteroarylrings of Z¹ and Z² are optionally substituted with one-to-three of anyone or combination of the following: halo, hydroxy, sulfhydryl,(C₁-C₃)-alkoxy, (C₁-C₃)-alkyl, (C₁-C₃)-alkylthio, trifluoromethyl,trifluoromethoxy, cyano, carboxy, carboxy(C₁-C₃)-alkyl, carbamoyl, orsulfamoyl; W is a covalent bond, O, S, SO, SO₂, CH₂, CHOH, CO, or NH;U¹, U², U³, U⁴, and a carbon atom form a five-membered heteroaryl ring;wherein one of U¹, U², U³, and U⁴ of the five-membered heteroaryl ringis covalently bonded to the R² group; wherein the U¹, U², U³, or U⁴ thatis covalently bonded to the R² group is a carbon atom or a nitrogenatom; wherein when the U¹, U², U³, or U⁴ that is covalently bonded tothe R² group is a nitrogen atom, one, two, or all of the other three ofthe group consisting of U¹, U², U³, and U⁴ is N and each remaining ofthe group consisting of U¹, U², U³, and U⁴ that is not N is C—R⁶;wherein when the U¹, U², U³, or U⁴ that is covalently bonded to the R²group is a carbon atom, one of the other three of the group consistingof U¹, U², U³, and U⁴ is N—R⁶, O, or S, and each of remaining of thegroup consisting of U¹, U², U³, and U⁴ is C—R⁶ or N; Y⁴ is O, S, orN—R⁷; each R⁶ is independently hydrogen, methyl, trifluoromethyl, oramino; and each R⁷ is independently hydrogen or methyl.
 62. A compoundof claim 61, wherein Y⁴ is S.
 63. A compound of claim 62, wherein W is acovalent bond.
 64. A pharmaceutical composition comprising a compound ofclaim 61, or an equivalent thereof.
 65. A method of treating a diseaseor condition mediated at least in part by prostaglandin D₂ produced byH-PGDS, in a subject in need of such treatment, comprising administeringto the subject a therapeutically effective amount of a compound of claim61.
 66. The method of claim 65 wherein the disease or condition isallergy or allergic inflammation.
 67. The method of claim 65 wherein thedisease or condition is asthma.
 68. The method of claim 65 wherein thedisease or condition is Duchenne muscular dystrophy.
 69. Apharmaceutical composition comprising a compound of claim 61, and asecond pharmacologically active compound.